2016 Clinical Nuclear Medicine in Pediatrics PDF

Clinical Nuclear
Medicine
in Pediatrics
Luigi Mansi
Egesta Lopci
Vincenzo Cuccurullo
Arturo Chiti
Editors
123
Clinical Nuclear Medicine in Pediatrics
Luigi Mansi • Egesta Lopci
Vincenzo Cuccurullo • Arturo Chiti
Editors
Clinical Nuclear
Medicine in Pediatrics
Editors
Luigi Mansi Vincenzo Cuccurullo
Nuclear Medicine Nuclear Medicine
Second University of Naples Second University of Naples
Napoli Napoli
Italy Italy
Egesta Lopci Arturo Chiti

Nuclear Medicine Nuclear Medicine
Humanitas Research Hospital Humanitas Research Hospital
Rozzano Rozzano
Milano Milano
Italy Italy
ISBN 978-3-319-21370-5 ISBN 978-3-319-21371-2 (eBook)

DOI 10.1007/978-3-319-21371-2
Library of Congress Control Number: 2015953158
Springer Cham Heidelberg New York Dordrecht London

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Foreword
Life-threatening disease is rare in pediatric patients. When it occurs it is complex

to manage and devastating for the patient and the family. To care for the patient,
age-appropriate techniques for diagnosis, staging, and therapy, as well as the
most experienced pediatric practitioners, should be available. This textbook is
written to provide nuclear medicine physicians with the information necessary to
deliver timely and appropriate care to children with these serious illnesses. Each
chapter is written by recognized experts in their subspecialty of pediatric nuclear
medicine.
The textbook is comprised of 20 chapters. The topics covered range from standards
published by international organizations about indications and technical factors to per-
form each study, to considerations about possible long-term effects of diagnostic and
therapeutic ionizing radiation exposure, to detailed discussions about procedures in
specific diseases.
Clinical chapters describe the circumstances where radionuclide procedures
can provide data for patient management. Technical information about patient
preparation, administered dose of the radiopharmaceutical, interval between
injection and imaging, and approaches to interpret the images are provided. In the
sections describing radionuclide therapy procedures, the authors focus on impor-
tant developmental and social aspects of management. This includes providing
essential information about the therapy rooms (and if possible a pretreatment
visit), a chance to meet the staff, the requirements for specialized nursing, and
participation of radiation physicists. The authors also provide suggestions about
meeting with the patients’ family to instruct them about how to prepare their child
for the procedures.
The text presents information on both benign and malignant conditions. In
the chapters on pediatric cancer, the authors describe the clinical presentation
and genetic abnormalities associated with the tumor and information that can be
gleaned from radionuclide procedures at the time of diagnosis, staging, and in
follow-up surveillance.
v
vi Foreword
Dealing with severely ill children is complex and difficult. By providing key
information about performing procedures in the safest and most appropriate fash-
ion, this textbook makes an important contribution to pediatric nuclear medicine.
H. William Strauss, MD
Attending Emeritus, Molecular Imaging and Therapy Service,
Memorial Sloan Kettering Cancer Center, New York, NY, USA
Professor of Radiology, Weill Cornell Medical Center, New York, NY, USA
Contents
1 Peculiar Aspects and Problems of Diagnostic

Nuclear Medicine in Paediatrics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Luigi Mansi, Vincenzo Cuccurullo, and Maria Rosaria Prisco
2 PET/MR in Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
Marco Salvatore, Carmela Nappi, and Alberto Cuocolo
3 Current Issues in Molecular Radiotherapy in Children . . . . . . . . . . . . 29
Mark N. Gaze, Jennifer E. Gains, and Jamshed B. Bomanji
4 Radiation Risk from Medical Exposure in Children . . . . . . . . . . . . . . . 51
Michael Lassmann and Uta Eberlein
5 Pediatric Nuclear Medicine in Acute Clinical Setting . . . . . . . . . . . . . . 61
Reza Vali and Amer Shammas
6 Nuclear Medicine in Pediatric Cardiology . . . . . . . . . . . . . . . . . . . . . . 115
Pietro Zucchetta
7 Endocrinology: Diagnostics in Children and Adolescents . . . . . . . . . 127
Giovanna Weber and Maria Cristina Vigone
8 Radionuclide Studies with Bone-Seeking Radiopharmaceuticals
in Pediatric Benign Bone Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139
Diego De Palma
9 Nuclear Medicine in Pediatric Gastrointestinal Diseases . . . . . . . . . . 149
Angelina Cistaro and Michela Massollo
10 Nuclear Medicine in Pediatric Nephro-urology . . . . . . . . . . . . . . . . . . 173
Pier Francesco Rambaldi and Pietro Zucchetta
11 The Problem of Cancer in Children . . . . . . . . . . . . . . . . . . . . . . . . . . . 185
Marta Podda, Veronica Biassoni, Cristina Meazza,
Elisabetta Schiavello Serena Catania, and Maura Massimino
12 Lymphoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239
Egesta Lopci and Arnoldo Piccardo
vii
viii Contents
13 Neuroblastoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255
Vittoria Rufini, Maria Vittoria Mattoli, and Maria Carmen Garganese
14 Pediatric Sarcomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 279
Natale Quartuccio, Leonard Wexler, and Heiko Schöder
15 Cerebral Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 301
Alice Lorenzoni, Alessandra Alessi, and Flavio Crippa
16 Thyroid Cancer in Childhood and Adolescence. . . . . . . . . . . . . . . . . . 317
Robert Howman-Giles and Christopher Cowell
17 Other Neoplasms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 337
Hossein Jadvar and Barry L. Shulkin
18 Diagnostic Imaging in European Eastern Countries:
a Russian Experience . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 349
L.S. Namazova-Baranova, A.A. Baranov, I.E. Smirnov,
A.V. Anikin, A.N. Getman, A.K. Gevorkyan, N.L. Komarova,
O.V. Kustova, O.V. Komarova, E.V. Komarova, and E.V. Antonova
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 371
Peculiar Aspects and Problems
of Diagnostic Nuclear Medicine 1
in Paediatrics
Luigi Mansi, Vincenzo Cuccurullo, and Maria Rosaria Prisco
Contents
1.1 Nuclear Medicine as Molecular Imaging 2
1.2 Cost/Effectiveness in Diagnostic Imaging 4
1.3 Cost/Effectiveness of Nuclear Medicine in Paediatrics 5
1.3.1 General Capabilities of NM 6
1.3.2 General Limitations of Nuclear Medicine 6
1.4 Technical Problems of NM in Paediatrics 7
1.4.1 How to Approach the Paediatric Patient in Nuclear Medicine 7
1.4.2 The Paediatric Environment in Nuclear Medicine 9
1.4.3 Patient Preparation 10
1.4.4 Patient Positioning 10
1.4.5 Patient Restraining 11
1.4.6 Sedation (and Narcosis) 11
1.4.7 Radioactive Dose 11
1.4.8 Image Acquisition and Other Technical Points 12
1.5 Nuclear Medicine in Paediatrics as Compared with Alternative Procedures 12
1.5.1 Risks and Prejudices 13
1.5.2 Peculiarities of Alternative Diagnostic Procedures in Paediatrics 14
1.6 Nuclear Medicine in the Diagnostic Scenario in Paediatrics 16
References 17
L. Mansi (*)
Nuclear Medicine Unit, Department of Clinical and Experimental Internistic
“F.Magrassi, A.Lanzara”, Second University of Naples, Naples, Italy
Medicina Nucleare, Seconda Università di Napoli
P.zza Miraglia, 2-80138, Naples, Italy
e-mail: luigi.mansi@unina2.it
V. Cuccurullo • M.R. Prisco
Nuclear Medicine Unit, Department of Clinical and Experimental Internistic
“F.Magrassi, A.Lanzara”, Second University of Naples , Naples, Italy
© Springer International Publishing Switzerland 2016 1

L. Mansi et al. (eds.), Clinical Nuclear Medicine in Pediatrics,
DOI 10.1007/978-3-319-21371-2_1
2 L. Mansi et al.
1.1 Nuclear Medicine as Molecular Imaging
In the third millennium, diagnostic imaging is becoming a match field where there
is no more only fighting between alternative techniques, as it was typical in the past
decades. In fact, in the definition of a rational diagnostic workup, it is today consid-
ered more productive to search for cooperative elements and points of convergence.
Many are the reasons for this Copernican revolution, having as major result the
creation of the new paradigm called “tailored medicine”, centred on the patient and
no more on the disease [1].
The first motivation is certainly dependent on the extremely fast technological
evolution and in particular on the new opportunities, incredible only few years ago,
allowed by computers. The change from analogical to digital imaging, representing
by now the standard also for old techniques, as traditional radiology, created new
premises that have been particularly productive in the creation of hybrid images,
more recently producible also using hybrid tools.
A second major improvement has been reached in the field at the same time
technological and cultural. In the recent past, diagnostic imaging was centred on
the anatomical and pathological gold standard. In this sense, the major contribution
to diagnosis was mainly due to morphostructural techniques, such as computed
tomography (CT), ultrasounds (US), magnetic resonance (MRI) and traditional
radiology (Rx). The information achievable with functional techniques was con-
sidered less relevant and more frequently intended as a second diagnostic level.
The advent and the diffusion of positron emission tomography (PET), since the
1980s, and in particular the evidence of the pivotal clinical information obtainable
with the glucose analogue F-18 fluoro-deoxy-glucose (FDG), have significantly
changed the general approach to the disease, with main, but not exclusive, rele-
vance in oncology.
In fact, thanks to FDG, tracing glucose, and to PET scanners, and acquiring
images with a higher sensitivity and spatial resolution with respect to traditional
machines, the great general advantages of radionuclide techniques have appeared
more evident. At first, functional information given by NM may precede pathologi-
cal changes, therefore allowing an earlier diagnosis with respect to morphostruc-
tural techniques. Furthermore, being the pathophysiological information also
expression of a prognostic content and more strictly connectable with therapeutic
strategies, it is possible to better define disease characteristics in individuals, acquir-
ing data better allocable within the new scenario of the tailored medicine.
It has to be pointed out that the PET revolution has revalued the whole NM acting
as tip of the iceberg, stimulating a new point of view. In fact, the relevance of func-
tional information achievable by PET-FDG highlighted the true core of radionuclide
procedures, i.e. its “molecular” content, previously hidden and not obvious.
Nuclear medicine is able to provide a molecular imaging since its clinical origin
in the 1940s, starting from the use of the first utilized radiopharmaceutical, I-131
iodide; going back to older historical premises, associated with the Nobel graduate
George de Hevesy, who firstly introduced the concept of radiotracer, these abilities
may be individuated as founding essence of our discipline. Therefore, although the
1 Peculiar Aspects and Problems of Diagnostic Nuclear Medicine in Paediatrics 3
term is actually more frequently referred to advanced procedures, mainly preclinical

and applied in the “omics” categories, molecular imaging could be considered, at
least in humans, almost a synonymous of nuclear medicine.
Living creatures are made by biomolecules in dynamic equilibrium between
themselves. This condition, called homeostasis, is studied by physiology, while the
unbalanced situation, i.e. the disease, may be evaluated and understood by patho-
physiology [2].
The best way to perform an in vivo “molecular” analysis is to use tracers, i.e.
molecules having an almost identical (when utilizing isotopes of the same atom) or
however similar chemical structure with respect to the native molecule. This condi-
tion may determine a “biological identity or analogy”, indispensable to produce an
almost overlapping in vivo kinetic, with the maintenance of the functional activity
which characterize the molecule that has to be studied.
A molecular imaging requires a further condition: the labelling of the tracer with
a tag strongly linked, without altering its biological behaviour, which allows its
visualization from outside of the body. This possibility may theoretically hold all
diagnostic techniques. As examples, a tracer for CT may be labelled with iodine,
MR contrast media may include a paramagnetic atom, tracers for US may be based
on microbubbles, optical imaging (OI) can make use of fluorescent agents and
nuclear medicine tracers may be labelled with radionuclide. Unfortunately, the
availability of a labelled tracer which maintains the functional activity of the native
molecule is a necessary but not sufficient condition in producing a clinically useful
in vivo image. In fact, to avoid an influence on the molecular process that has to be
studied or else to prevent toxic effects, the administration of a little number of trac-
ing molecules with respect to the number of native molecules involved in the system
under evaluation is requested. Generally, the administered tracer’s quantity has to be
in the order of pico or nanomoles, a ponderal amount at present only associable with
the tracers used in optical imaging and nuclear medicine. Nevertheless, although it
has its own fascinating premises, allowing a molecular imaging up to the omics
level, OI is affected by a major problem for a clinical use in humans: the non-
penetration of light photons through the body. Therefore, OI may produce intrigu-
ing results in preclinical imaging or in evaluating superficial layers, as the skin, eyes
or mucosa, when using endoscopic techniques, but, using this approach, the meta-
static involvement of a liver by external probes cannot be detected.
As consequence, at present, nuclear medicine may interpret a primary role in
the modern diagnostic imaging, being the most effective in producing an in vivo
molecular imaging able to detect or characterize the majority of human diseases. It
has however to be pointed out that NM doesn’t exert its clinical role always through
a molecular approach; in many cases radiopharmaceuticals concentrate on the
basis of non-metabolic mechanisms, such as those associated with nanocolloids
subcutaneously injected to individuate sentinel lymph nodes or with albumin mac-
roaggregates intravenously injected to diagnose a pulmonary embolism. Even so,
also in these cases, the image is an expression of a concentration’s difference and
never of a density’s variation, as it happens using morphostructural techniques. In
this sense, while using, for example, standard CT, it is not possible to distinguish a
4 L. Mansi et al.
living body from a corpse, radionuclide procedures are only feasible in living crea-
tures. As consequence, being based on pathophysiological premises, functional
images can produce an earlier diagnosis or provide complementary information on
prognosis and on the relationship with therapy with respect to the one obtained
with morphostructural exams. Conversely, because the image in nuclear medicine
doesn’t represent differences in density, but in concentration, the anatomical detail
is typically poor, being furthermore impossible the topographic analysis of the
relation between contiguous structures not showing a radiotracer’s uptake. As
example, when using a radio-colloid which concentrates in the liver and spleen, it
is not possible to evaluate the spatial relationship with the adjacent right kidney,
non-concentrating the radiocompound. For these reasons, it has been a major
improvement in diagnostic imaging the advent of a digital system that allows the
production of fused images showing together either the pathophysiological and the
morphostructural content. Even more the commercial availability of hybrid
machines has been a revolution, producing almost simultaneous images obtained
with radiological and nuclear medicine tools allocated in the same gantry.
Does it mean that the toolbox of diagnostic imaging, because of the great pre-
rogatives of radionuclide studies and of the integrated information given by hybrid
scanners, may be today only filled with nuclear medicine instruments? The answer
is certainly no.
To better understand this point, it is appropriate to introduce the concept of cost/
effectiveness.
1.2 Cost/Effectiveness in Diagnostic Imaging
A cost-effectiveness analysis (CEA) evaluates relative costs and outcomes in the

comparison between two or more lines of action. It is typically used in the medical
field, where a cost-benefit analysis, more strictly connected with a monetary value
in measuring the effect, may be unethical. Nevertheless, health is priceless.
Healthcare has a budget that unfortunately is too low to answer to all health requests.
Therefore, the goal is to give a sustainable response, hopefully effective, to the larg-
est number of subjects, being impossible to provide the best to all of them.
A cost-effectiveness analysis in medicine is conditioned by a large series of
items, starting from the general scenario where priorities have to be chosen. In this
context, widely varying in different countries, the worst condition may derive from
the absence of funding necessary to support the health system, as it especially
occurs in third-world countries. Unfavourable may also be the context for poorest
people in countries where the health system is mainly based on private contribu-
tions, being scarcely guaranteed welfare policies. Unfortunately, because of very
high and ever-increasing general costs dependent by many issues, as population
ageing and rising value of health facilities, very difficult choices may occur also in
the best health systems, which may however fail to fully satisfy the demand for
health. This negative trend can lead to the possible exclusion from the right to health
of “weak” categories, such as older patients with a limited life perspective, mainly
when nonautonomous and affected by chronic diseases, infants with rare diseases
and individuals requiring the utilization of very expensive drugs, tools and proce-
dures, unsustainable for the general population.
It is not the aim of this chapter to discuss more widely and deeply this very rel-
evant issue. Major points for reflections are however to be introduced to create a
new culture able to optimize the distribution of available resources.
The first change of the way of thinking is to consider the cost not as the sum of
prices of the different techniques separately taken. Using this traditional approach,
the first choice is frequently directed to the cheapest technique, often not having the
capability to solve alone the clinical problem. As consequence, an increasing cost
will derive from the addition of further procedures, from a delay in diagnosis and
eventually of hospitalization times and from the choice of a less effective (and fre-
quently more expensive) therapeutic choice. It is therefore important to learn to
have an a priori vision of the whole diagnostic and therapeutic tree, individuating
the most effective course.
The second cultural revolution has to be centred on the understanding of the
concept “tailored medicine”. The true consequence of this vision, having the
patient in the centre of the medical reasoning, is to introduce in the way of think-
ing the knowledge of the probability of disease for each individual patient, trying
also to understand a priori which could be the best therapeutic choice. In general,
this capability is strictly associated with diagnostic procedures giving not only a
diagnosis but also an information connected with prognosis and therapy. This is
what happened with the so-called functional techniques, first of all with nuclear
medicine.
These issues should be taken in consideration in each context and for each clini-
cal indication, as it can be read in the following chapters. In this script we want to
refer to the most frequent policy carried out in the specific field of paediatrics, as it
has to be applied in the so-called advanced and emerging countries, where a state-
of-the-art standard diagnosis may be achieved routinely.
1.3 Cost/Effectiveness of Nuclear Medicine in Paediatrics
As it can be read in Table 1.1, the clinical role of a procedure is at first dependent on
its own capabilities and limitations.
Table 1.1 Conditions determining Its own capabilities and limitations

the choice of a diagnostic procedure
Capabilities (and limitations) of alternative procedures
in a clinical workup
Clinical questions:
Diagnosis, prognosis, connection with therapy
Local scenario:
Instruments and procedures routinely used
Epidemiological and socio-economic issues
Risks and prejudices
6 L. Mansi et al.
1.3.1 General Capabilities of NM
In the paragraphs above, we described how effective nuclear medicine can be

because of its capability to produce a molecular and/or pathophysiological imaging.
Furthermore, with respect to other procedures, as the US, NM is advantaged because
it is reproducible and not operator dependent. This point in favour is also accompa-
nied by a panoramic view, not allowed by US. Furthermore, mainly in case of posi-
tive indicators, as FDG and Tc-99 m diphosphonate, showing a more intense uptake
in pathological tissues with respect to the normal ones, a whole-body scan, very
helpful in staging and restaging, may be acquired. Using radionuclide techniques is
also standardizable and therefore more reliable quantitative analyses, allowing a
better evaluation of nonfocal diseases and/or a more precise definition of changes
which appear in the follow-up, eventually as response to therapy.
A further positive issue connected with NM is dependent on the capability to
define a prognostic information, as it happens with FDG in oncology. Using radio-
compounds, as FDG or radiolabelled white blood cells (WBC), is also possible to
define disease activity in many chronic inflammatory conditions, finding a relevant
role in recruiting only patients that may successfully undergo to therapies. With
respect to therapeutic strategies, a major advantage may be acquired in the presence
of radiopharmaceuticals that may be labelled either with γ or β + emitters and with
β-radionuclides, as it happens for radioiodine, metaiodobenzylguanidine (MIBG)
and somatostatin analogues. Using this approach, it is possible to forecast a thera-
peutic efficacy, on the basis of an a priori evaluation obtained with a similar radio-
compound, administered at a significantly lower radiation dose. As reported above,
the complementary contribution given in prognosis and therapy may create a clini-
cal indication for NM also as second-line diagnostic procedure after a first “patho-
logical” diagnosis has been already obtained.
1.3.2 General Limitations of Nuclear Medicine
Being based on difference of concentration and not of density, NM cannot give an

anatomical information. Moreover, radionuclide procedures don’t allow a loco-
regional staging, mandatory before a surgical choice, as an example to individuate
relationships between mass and adjacent vessels. Many of these limitations have
been recently solved by the availability of hybrid machines, including PET/CT,
SPECT/CT and more recently PET/MRI, which permitted a significant increase in
accuracy, either decreasing false-negative or false-positive results, with respect to
the individual procedures considered alone.
A major limitation associated with NM is certainly related to the presence of
ionizing radiations, a disadvantage shared with CT and traditional Rx. Nevertheless,
in the presence of an effective clinical indication, there are no absolute contraindica-
tions for radionuclide techniques, although radioisotopic procedures have to be
always “justified”. It means that no scintigraphies or PET or SPECT studies may be
performed when alternative procedures permit the achievement of a similar
information without radiations. This rule is more restrictive in paediatrics (and even
more in pregnant women), being the stochastic risk associated with nuclear medi-
cine conditioned either by the percentage of cells that multiply, higher in infancy, or
by the life expectancy, longer for paediatric patients. It has however to be pointed
out, as we will see below in the paragraph evaluating risks, that the calculation of a
cost/effective balance is not always easy, mainly in comparison with MRI, nega-
tively affected by a minor diffusion and frequently accompanied by higher costs and
by a high rate of studies non-executable in paediatrics without narcosis.
As a negative counterpart for nuclear medicine, it has to be remembered that
problems for radioprotection may be increased considering the radiation charge for
physicians, nurses, technicians and relatives or other caregivers, the presence of
which may be requested to facilitate the procedure. In this sense, although the dose
of radiation and an increasing incidence of cancer are typically very low, a justifica-
tion is mandatory both for the patient and for accompanying persons.
1.4 Technical Problems of NM in Paediatrics
Although they are not exclusive of paediatric patients and not present in all the sub-
jects, also because of the wide differences existing, for example, in early childhood
with respect to the adolescence, some technical problems are peculiar in this popu-
lation; they may be due to factors such as the body’s structure and size; difficulties
in injecting radiopharmaceuticals, due to the small calibre and fragility of the ves-
sels; inability to collaborate which may cause disturbing movements or an increased
risk of contamination; psychological structure frequently governed by fear of the
unknown; and so on.
While it is impossible to exclude ionizing radiations from radionuclide studies,
to perform a study allowing an effective clinical response at the lowest cost, which
has also to consider risks and the reliable solution of technical problems, it has to be
a professional duty [3].
1.4.1 How to Approach the Paediatric Patient in Nuclear

Medicine
In paediatric imaging, a successful diagnostic examination is obtained when the

achievement of quality images, without degradation due to technical problems,
occurs without mental or physical detriment to the patient. The ability of a child to
remain sufficiently immobile during the scan depends upon his or her behaviour and
the administered technique itself. Infants and small children are unable to cooperate
and to follow verbal directions. Many older children are cooperative with adequate
support and guidance during the exam.
It has to be remembered that paediatric patients in the NM department are often
subjected to unexpected procedures that cause pain and increased anxiety and dis-
tress, like intravenous or subcutaneous injections and urethral or angiocatheter
8 L. Mansi et al.
insertions. The use of topical creams to provide topical anaesthesia has been shown
to reduce the pain associated with these procedures. Conversely, anaesthesia has to
be avoided as much as possible, because, although it may allow a “technically per-
fect” scan, it is dangerous and expensive. Furthermore, it may negatively affect the
examination conditioning the pharmacokinetic of the injected radiotracer. Similarly,
sedation has to be performed only exceptionally and when absolutely needed,
because of serious associated risks, such as hypoventilation, apnoea, airway obstruc-
tion, laryngospasm and cardiopulmonary impairment. These adverse reactions,
which may occasionally occur during and/or after sedation, can be minimized with
a procedure carefully performed, but not completely eliminated.
Children’s weight varies from premature neonates, weighing less than 1 kg up to
100 kg and more in teenagers. This condition creates a huge diversity in physiology,
pathology and psychology. Therefore, starting from the arrival of the patient in the
department, a sufficient time is needed to allow an individual assessment, based on
many issues as an interactive discussion in acquiring a consent, including the activa-
tion of special preparation procedures to the exam, such as a play therapy.
When possible, information about the procedure should be given beforehand
through information sheets sent to the family or through a phone call with prepara-
tion instructions. In general parents, or other close relatives such as grandparents
and uncles, may better help the children when they are prepared as well. Therefore
the procedure has to be explained to the parent (and/or to the alternative caregiver),
and any question or concern has to be addressed as required. It is essential to give to
the accompanying person the sufficient time to ask questions or express concerns at
any point, particularly when one is dealing with frightened or anxious children, who
may be less cooperative if they do not understand what is happening to them.
Conversely, it is important to restrict the number of interacting relatives, individuat-
ing only one or two of them as possible caregiver, to avoid confusion and the activa-
tion of negative behaviours [4].
A child-friendly approach and patient preparation are major issues for the suc-
cess in the large majority of nuclear medicine procedures. Children should be pre-
pared for what they will face, to lessen their anxiety and promote their cooperation.
Such preparation should be based upon the developmental level of the child. The
role of the parent should be supported when possible. Most kin and children have a
desire to be together during procedures. Policies should be developed to offer this
opportunity. The presence of a parent is comforting to a child and can lessen anxi-
ety. Allowing a protective person to remain in the room during the scan time can
also give the child a sense of security, helping an otherwise uncooperative subject to
successfully complete the scan without the need for sedation. It can be also helpful
to allow the little patient to bring a favourite toy or stuffed animal into the scanning
room, if possible. This toy can be placed above the head of the subject or held in his
or her hands, out of the field of view.
Children need to know what will be required to them to gain their cooperation.
Therefore they should be prepared for the experience they will encounter in the
nuclear medicine department. They should be given an age-appropriate explanation
of what they will feel, hear, see and/or taste. Medical and paramedical personnel
should provide encouragement and ample praise. The subjects should be approached
with the positive expectation of success, to increase the rate of cooperative scans.
Distraction is a commonly used non-pharmacologic pain and fear management
technique used by both healthcare professionals and parents to attenuate procedural
hurt and distress. Distraction operates on the assumption that, by shifting a child’s
focus to something engaging and attractive, his or her capacity to attend to painful
stimuli is hindered. Thereby pain, distress and anxiety are reduced. A number of
behavioural distraction techniques, such as watching a movie, listening to a story, or
listening to music, can increase the child’s ability to tolerate the examination.
Natural sleep in infants can be induced by food, comfort and warmth and represents
a condition greatly facilitating the scan.
When restraining a child, it is important not to use excessive strength; the used
force should be appropriate to the child’s age. The safety of the staff restraining a
strong patient is also paramount to good practice. Training of professionals in effec-
tive risk minimization when restraining should be given. As with any paediatric
procedure, intravenous access can be problematic depending on patient cooperation
and hydration status. Establishing an intravenous line before injection allows the
little patient time to recover, as the experience can often be painful and stressful. All
the personnel involved with the patient should be familiar with the patient’s posi-
tioning, having also knowledge on the scan’s duration. Medical equipment and
patient intravenous lines have to travel safely with the patient through the scanner,
to maintain the patient safety and to have the capability to intervene, if necessary.
Once scanning is complete, images should be reviewed before the patient is
transferred off the scanning bed, to ensure that no further imaging is required.
The management of uncooperative children should take into account their indi-
vidual needs and fears, within the context of the illness, and in partnership with the
parents or guardians. Ideally, the wishes of the child should be respected, and, if a
competent subject is resistant to the persuasive powers of parents and professionals,
the investigation must be delayed and reassessed [5].
1.4.2 The Paediatric Environment in Nuclear Medicine
If the disease “scares”, this happens even more frequently for younger patients, who
have a greater fear of the unknown. In this sense, it is very important to create a
familiar environment, where colours, lights, waiting rooms and tools of distraction,
including televisions, toys, cartoons and so on may play an important role in creat-
ing an atmosphere of relaxation, in which the smiling staff professionalism is a
fundamental added value. Of course, an important element favouring this goal is
determined, as widely explained above, by the communication with the patient,
when big enough to understand, and/or with his or her relatives. If part of the fear is
connected with the unknown, the a priori knowledge of the steps that will be lived
in the next few minutes or hours can certainly increase the collaboration of the
young patient. As previously reported, it is very important to have interactive con-
nection with the relatives that have to be tranquilized and eventually may be
10 L. Mansi et al.
authorized to keep company to the kid after correct information of risks associated
with ionizing radiations. In this sense, while a pregnant mother should never get in
the authorized “hot” area, the cooperative participation of grandparents has to be
stimulated with respect to the presence of younger caregivers. Of course, the contri-
bution of nurses, technicians, physicians and/or other professionals involved may be
requested, if needed. Considering that fear, pain, family dynamics, previous experi-
ence with diagnostic and therapeutic strategies can determine problems, it’s impor-
tant to work for the best understanding of the procedure, trying to determine the
more strict cooperation between all the actors of the study, first of all with the little
patient. A psychological expertise by the physicians and professionals involved is
very important, because information of the patient and of caregivers may also
become detrimental, mainly in case of anxious subjects. A mandatory rule is never
leave the children unattended.
1.4.3 Patient Preparation
With respect to the intravenous injection, the most important rule is never inject
radioactive if you’re not sure you’re in the vein. To reach this goal, strategies utiliz-
ing butterfly needles and/or three-way catheters are helpful, and these operations
have to be performed in the more relaxed situation, before the injection of the radio-
pharmaceutical. Of course, this suggestion is particularly critical when dynamic
studies have to be acquired. We will not discuss here, devoting this information to
following specific chapters, other invasive and painful procedures, such as the ure-
thral catheterization in radionuclide cystography. We want only to remember that all
the strategies having as their aim the reduction of pain and/or of risks of infection
have always to be adopted. In this context, have also to be evaluated conditions that
may reduce radiation dose to the patient, as those related to hydration and urinating.
The risk of contamination has to be avoided using impermeable sheets. Similarly,
the need of fasting; the knowledge of haematochemical data, as glycaemia before a
PET-FDG scan; and the eventual relevance of the suspension of a therapy have to be
well known before the radiocompound’s administration.
1.4.4 Patient Positioning
This is a major technical issue in paediatric imaging, because a correct position is

essential not only for the anatomic evaluation but also to reduce the acquisition
time. Positioning is also critical to determine the best counting rate from the inter-
ested area. In this sense, it is very important to define a field of view minimizing the
contribution on the count rate coming from outside the area that has to be studied.
This strategy is particularly important in presence of a possible activity in the blad-
der that has therefore to be emptied when possible. It has also to be remembered that
a zoom may better define the image but doesn’t avoid the counting of radiations
emitted outside of the field of interest, if they are included in the field of view.
1.4.5 Patient Restraining
Movements create problems either in the definition of the signal to noise ratio
and in the construction of a reliable image, obtainable with a satisfactory spatial
resolution. This is particularly true for dynamic and tomographic studies, with
main respect, because of the worst technical condition, for SPECT with respect
to PET.
To solve these problems, a solution that has to be carefully considered for each
individual patient can be the restraining (in proper anatomic position); clearly this
strategy is more useful, and sometimes mandatory, in youngest subjects. The immo-
bilization system has to be efficient but comfortable (avoiding forcible restraint),
also because crying can determine movement. Of course, when possible, this tech-
nical supplement is preferably to be avoided; in older kids a cooperative interaction
either with the patient or with his or her caregivers may create a more favourable
operative condition. A possible alternative to restraining, generally applicable in
kids up to 24 months, is to hold the infant. When needed the restraining may be
performed with different tools, as using sandbags and Velcro straps.
1.4.6 Sedation (and Narcosis)
Being radionuclide procedures based on pathophysiological premises, sedation may

determine a disturbing effect in pharmacokinetics of some radiotracers. In this
sense, it has to be utilized only if really needed and in the absence of alternative
strategies which may avoid the administration of drugs. In general, this condition
may be required only in children of 4 years or less and only in limited non-
collaborative case. This request can be mainly indicated in whole-body and SPECT
examinations. In the majority of cases, sedation may be averted in older patients, if
there is an interactive cooperation with the subject, having been explained with the
procedure carefully.
When performed, the sedative procedure should be administered by personnel
trained in paediatrics anaesthesiology and resuscitation. In the following phase,
skill and experience of nursing staff (and eventually of nuclear physicians), which
guarantees a careful monitoring, limit the risks.
1.4.7 Radioactive Dose
This book is presenting a specific chapter on dosimetry. Here we want only to

express some general suggestions. The two main rules are apparently contradicto-
ries: any dose must be calculated to avoid radiation overexposure, but at the same
time the dose has to be calculated, avoiding the risk of injecting an activity too low
to produce clinically useful images. This situation has also to consider the amount
that remains in the syringe and the possibility of extravasation. Therefore, as it will
be better explained in the next chapters, although the paediatric dose should be
12 L. Mansi et al.
calculated proportionally to the dosage of the adult, with reference on body surface
area (BSA) preferably with respect to weight, a minimal threshold activity higher,
mainly in littlest patients, with respect to the mathematically calculated dose has to
be considered. Similarly, a more careful evaluation has to be done when the injec-
tion is performed as bolus in dynamic studies, being more frequent in these cases
the probability of inappropriate administration [6, 7].
1.4.8 Image Acquisition and Other Technical Points
Differences in image acquisition between adult and children are relatively few. To
improve the signal to noise ratio, in some cases, the use of a camera with a little field
of view can be preferred, determining a count rate more strictly dependent on the
region that has to be studied. A further peculiarity, almost lost with the advent of
SPECT systems, is connected with the use of collimators. As an example, the pin-
hole has been widely utilized in paediatric nuclear orthopaedics, while collimators
with a higher sensitivity may be preferred in cases when a faster scan, a lower dose
and the recovery of a static examination in case of a radiocompound’s extravasation
may support the choice of a highest sensitivity with respect to a better spatial resolu-
tion. To acquire a more standardized study, less influenced by individual variations
and movement, planar scintigraphy using multiple projections may be sometimes
preferred with respect to SPECT, as how it happens in many centres for renal scar
detection.
A further difference with respect to the adult may be individuated in dynamic
studies. A typical example may be found in the use of sequential renal scintigra-
phy. In case of a “partially” wrong injection, however, allowing the acquirement
of the most relevant clinical information requested by the clinician, a second
injection is in general contraindicated. In these subjects, in the report, it has to be
referred how the technical problem has created the impossibility to acquire
reliable quantitative data.
1.5 Nuclear Medicine in Paediatrics as Compared

with Alternative Procedures
As it can be derived from Table 1.1, the role of NM in paediatrics is dependent on

the comparison with alternative techniques, which have the capability to answer to
the same clinical question. However, a possible utilization may be also justified as
supplementary contribution to diagnosis, when further relevant information, better
answering to a different question related to prognosis and therapy, may be obtained.
Of course, all the choices have to be made on the basis of a cost-effectiveness analy-
sis considering instruments, expertise and procedures routinely used in the specific
scenario where individual decisions may also be based on waiting lists and epide-
miological and socio-economic issues.
1.5.1 Risks and Prejudices
In the definition of a cost/effective balance in paediatrics, remembering the funda-

mental principle “primum non nocere” (first do no harm), the evaluation of associ-
ated risks has to be very critical. In this sense, techniques utilizing ionizing radiations
have to be utilized only when a similar information cannot be obtained from an
alternative procedure not utilizing radiations, as US. Nevertheless, it has to be
pointed out that the alternative utilization of MRI has to deal with the analysis of a
wider number of considerations, including higher cost, lower diffusion and exper-
tise and elevated technical complexity.
In this context, it has to be evidenced that risks deriving from ionizing radiations,
stochastic and not lethal, are only a little part, and certainly not the more dangerous,
of the risks that may be associated with diagnostic imaging. Nuclear medicine is not
affected by absolute contraindications, being diagnostic radionuclide examinations
performable in all the subjects, in the presence of a clinical justification, without
risks which may determine the patient’s death. Conversely, a patient may die
because of a reaction to the administration of contrast media used in traditional
radiology and CT or, also if more rarely, in MRI and ultrasonographic techniques.
High risks may be dependent on drugs or narcosis, the latter frequently required in
infants when performing MRI studies; subjects undergoing MRI may also face
problems due to eventual metallic components and/or to other tools influenced by
the magnetic field. Risks may also be associated with the administration procedure,
as it may happen in angiography, in endoscopy and, more in general, in invasive
approaches.
Together with risks associated with the diagnostic technique, even greater prob-
lems may be born in case of an unjustified delay in the activation and execution of
a diagnostic tree, of a too long duration of the whole diagnostic procedure, mainly
in emergency, because of the lack of resuscitation supports and expertise. Between
all possible risks, the greatest are certainly due to diagnostic mistakes. In this sense,
to avoid the choice of a radionuclide study because of the fear of ionizing radiations
may create in many cases an unfavourable cost/effective ratio, either in the diagnos-
tic course and/or in the definition of therapeutic strategies. In this sense, nuclear
medicine has to be considered a primary diagnostic support, for example, in cases
when it can reduce false-negative and false-positive results or when it can more
safely recruit patients that have to be hospitalized and/or avoid a too-early
discharge.
To make a rational choice including radionuclide techniques, it is however nec-
essary to uncover and destroy the prejudices against them. In other words, it is
important to fight against the so-called September 12’s syndrome [8], confusing
the risk with the irrational risk’s perception. According to this syndrome, in
September 12, 2001, i.e. the day after the criminal collapse of the twin towers in
New York, there was a huge decrease in the number of passengers by plane world-
wide. To destroy prejudices against radionuclide procedures, it has to be clarified
that nuclear medicine is at Hiroshima and Fukushima as a drug is to a poison.
14 L. Mansi et al.
It means that if radioactivity at a high dosage is certainly a danger, the very low
number of radiations associated with diagnostic radionuclide procedures may very
rarely determine a negative effect, either because of the low probability of a bio-
logical oncogenic mutation or of the great capability of humans to recover genetic
damages. To better understand this concept in a wider evaluation, it has also to be
remembered that dosimetry associated with diagnostic radionuclide procedures is
very low, determining stochastic risks favourably comparable to the large majori-
ties of those present in a day life. In particular, the radiation charge is comparable
with natural radiations: it has been calculated that the radiation dose given by a
renal scan is corresponding to that received by a pilot or a passenger flying for only
80 h. To give further information on comparative risks, epidemiological studies
have calculated that the number of deaths derived from diagnostic nuclear medi-
cine is very low (35–250 cases per million), corresponding to the number of deaths
associated with 3000 km in motorcycle, 75 min of climbing mountains and 17 h of
a day life of a 60-year-old man.
1.5.2 Peculiarities of Alternative Diagnostic Procedures

in Paediatrics
As noted many times above, in the definition of a cost/effective balance nuclear

medicine in paediatrics has to confront its peculiarities with qualities and limita-
tions of techniques having capability to answer to the same clinical question, being
clearly easier to individuate a diagnostic space for exclusive indications.
In this scenario, traditional Rx is advantaged because of its widely diffusion,
being as well cheap, fast and easy to be performed, also at bedside. For these rea-
sons, it may save also today a primary role as first-line technique in a little group of
indications, mainly concerning the chest and bone. Nevertheless, negatively affected
by ionizing radiations, traditional Rx only rarely allows a final diagnosis, with main
reference to pathologies affecting internal organs. With respect to the past, a more
limited clinical space is today identifiable for dynamic techniques, such as urogra-
phy and cystography. These procedures, having capability to provide a functional
information in the presence of a high anatomical resolution, may be mainly helpful
when a precise diagnosis of malformation has to be obtained. These studies are
affected by a high and frequently unjustified radiation charge and by major limita-
tions with respect to the corresponding radionuclide techniques, which allow a more
sensitive and precise result, also because of a better physiological and quantitative
content, obtained at a lower radiation dose. A competition further decreasing the
clinical interest may derive from the availability of functional studies performable
with MR, although not yet widely diffused [9].
By now consolidated awareness of the absence of side effects represents a major
undoubted advantage of ultrasound techniques in paediatrics. Being diffuse, cheap,
fast and easily performable, also at bedside, these procedures are proposed as first-
line methods for a large number of indications. Nevertheless, they are not feasible
in several patients and in some anatomical locations and most frequently require
further procedures to complete the diagnostic course. A major problem is dependent

on the fact that these methods are operator dependent, moreover not allowing a
panoramic view of the field of interest. This point may represent a major disadvan-
tage in paediatrics where a standard approach and a consolidated experience of the
operator may be mandatory in the solution of many difficult clinical problems. The
negative effect of this limitation on the achievement of the best cost/effectiveness
ratio can be understood by the evaluation of the ultrasonographic technique used for
the detection of the vesico-ureteral reflux (VUR), based on the intra-vesical admin-
istration of a contrast medium for US. The diagnostic information has to be obtained
following continuously for tens of minutes the possible reflux of the contrast from
the bladder to the kidneys. Unfortunately, being the method non panoramic, a path-
ological information can be lost when it occurs in the contralateral side with respect
to the one observed in that moment. Furthermore, because of the criticality of the
information in the decision of a therapeutic strategy, the procedure requires the
involvement of an expert sonographer for a too long a time, with negative effects on
costs and on the quality performance in other fields. Interestingly, as it will be better
described in one of the further chapters of this book, the most effective procedure in
detecting VUR is cystoscintigraphy, which has to be preferred for its higher sensi-
tivity, although the presence of ionizing radiations. Allowing typically a morpho-
structural information when performed using a standard approach, US may also
give functional data. Using Doppler and contrast media, useful information, also
quantitative, on flow, vascularity and perfusion may be acquired, although only
rarely they are conclusive in the diagnostic course.
Standard computed tomography (CT), largely diffuse in all the diagnostic depart-
ments, including emergency, represent at the present the most important technique,
mainly in oncology, for diagnosis, staging and restaging, occupying a central role in
guidelines. The procedure, also utilizing contrast media to increase the diagnostic
accuracy, is effective in a large number of patients, having capability to allow a
clinical result, useful to define the successive therapeutic strategy. As further advan-
tage, the technique is fast and well tolerated and therefore feasible in the majority of
cases without the need of narcosis or of other disturbing tools. A major quality may
be found in its panoramic view, being also the technique not operator dependent. As
limitations, contraindications for contrast media, a high radiation dose and the
scarce ability to provide functional information have to be remembered.
A great advantage in paediatrics for magnetic resonance techniques is deter-
mined by the absence of ionizing radiations. Furthermore, MR techniques allow a
multi-parametric imaging, further improved by the possible addition of functional
techniques either with or without the administration of contrast media. In this way
better information with respect to CT may be obtained in some fields, such as in the
evaluation of soft tissues and/or in analysing anatomical territories, as the head,
neck and pelvis, or diseases characterized by slight changes in density, as demyelin-
ating pathologies. Being less effective with respect to CT in evaluating the lung and
bone, MR is also affected by a scarce diffusion, high costs and technical complex-
ity; general contraindications include the presence of metallic components or pace-
makers, claustrophobia and so on. A major problem in paediatrics is derived from
16 L. Mansi et al.
the length of the examination and by difficulties occurring in the local support to the
little patient. As consequence a narcosis is frequently required, further complicating
the procedure and increasing associated risks. For these reasons CT is frequently
preferred, although the presence of ionizing radiations.
A particular evaluation has to be made in paediatrics for angiography and other
invasive approaches, which may represent the best approach, but only in a little
number of cases. The presence of severe contraindications and of high risks creates
the need to choose this approach only when other diagnostic strategies are not
effective.
1.6 Nuclear Medicine in the Diagnostic Scenario

in Paediatrics
As described above, the diagnostic scenario in paediatrics is occupied by very effec-

tive procedures, all of them with favourable peculiarities which support their pro-
posal in the diagnostic course. In particular, US are the most frequently utilized first
line; Rx can be cost-effective, mainly in the first evaluation of pulmonary and skel-
etal diseases; CT has a pivotal role in oncology; and MR and newer approaches
enlarged the clinical boundaries of “traditional” imaging also outside of the mor-
phostructural fence, having acquired the ability to allow also a functional and quan-
titative evaluation.
In this context nuclear medicine needs to express comparatively its qualities
[10]. At first, nuclear medicine is the only technique with an imaging exclusively
based on pathophysiological premises, feasible in all the patients, with a reproduc-
ible and reliable production of quantitative data. Having capability to evaluate the
living function of normal parenchyma and of pathological tissues, radionuclide pro-
cedures, when based on molecular uptake mechanisms, may define an early diagno-
sis and a better connection with prognosis and therapy. Being already in the clinical
field, the use of radiocompounds permitting the analysis of complex mechanisms,
such as neurotransmission, apoptosis and angiogenesis, has already gone through
the first steps in the road to the future of molecular medicine where genomics, pro-
teomics, pharmacogenomics and antisense and gene therapy will find their clinical
role. Furthermore, nuclear medicine has, with respect to alternative diagnostic tech-
niques, consolidated supremacy in defining accurate quantitative methods, which
may permit an increased diagnostic accuracy, a disease detection also in absence of
focal lesions, a better evaluation of therapy and/or of a prognostic evolution and a
better analysis of stress test [11].
Waiting for the full realization of a diagnostic scenario dominated by molecular
imaging, where nuclear medicine could play a major role, because of its abilities in
answering at best to questions made in a pathophysiological language, we have to
consider where its position today in the routine practice, in our actual working place.
In this scenario, NM can certainly give an important contribution in diagnosis,
further increased by the capability to better evaluate prognosis and the connection
with therapeutic strategies. The dominance in the diagnostic imaging scenario could
already start in many fields, first of all in oncology, thanks to the ever-wider diffu-
sion of molecular radiotracers that can be evaluated by hybrid machines, including
PET-CT, SPECT-CT and, with intriguing perspectives in paediatrics, PET-MRI.
To reach and consolidate a clinical role, NM has to demonstrate its capability to
answer to clinical indications with a cost/effectiveness ratio supporting its utiliza-
tion. In this direction, a further and wider diffusion of nuclear medicine depart-
ments, enriched by technologically advanced tools, acting 24 h a day for 365 days a
year, also in an emergency, has to be stimulated.
Different policies could be actuated for the diagnostic imaging in paediatrics. In
our opinion, although all nuclear medicine departments need to be expert in this
peculiar field, it could be important to individuate and develop centres with a high
workload of paediatric subjects where more easily and reliably can be guaranteed
a reliable and cost-effective approach; the high workload may more easily justify
the acquirement of expensive newest instruments particularly interesting in
younger subjects, as PET-MRI or the most advanced and performing PET-CT and
gamma cameras, allowing a faster and more accurate acquisition at a lower radia-
tion dosage [12].
Waiting for the future, we can give a future to our present favouring the under-
standing of qualities of nuclear medicine by the medical community and, more in
general, by the users. These qualities, strictly linked with our diamond procedures
as PET-FDG, are the essence of all the radionuclide techniques, including those
performed with a planar imaging. We have to demonstrate that for a large number of
clinical indications radionuclide procedures are cost-effective in giving useful and
original responses to the queries made by the prescriber.
Therefore, a crucial part of our future may be found in the aims of this book,
having as main goals the standardization of procedures, the education of nuclear
physicians and the interaction with the clinician, who has to understand how impor-
tant can be the contribution of nuclear medicine to his or her knowledge of the
disease and of the patient.
References
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man): could functional imaging redefine the brain of a “new human species”? Eur J Nucl Med
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toma and paraganglioma model. Eur J Nucl Med Mol Imaging 39(8):1262–1265
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lines. Radiology 261(2):347–349
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(2011) Pediatric radiopharmaceutical administered doses: 2010 North American consensus
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PET/MR in Children
2
Marco Salvatore, Carmela Nappi, and Alberto Cuocolo
Contents
2.1 Introduction 19
2.2 Available Diagnostic Tools in Pediatric Diseases 20
2.3 PET/MR in Pediatric Patients 21
2.3.1 Neurological Disorders 21
2.3.2 Oncological and Hematological Disorders 23
2.3.3 Cardiac Disorders 25
2.3.4 Fever and Inflammation of Unknown Origin 25
Conclusions 26
References 26
2.1 Introduction
The rapid increase in incidence of diagnosed malignant diseases in children over the
last decades, combined with innovations in molecular oncology, neuroimaging, and
hybrid imaging, has encouraged researchers and physicians to make a special effort
in optimizing technological resources to approach pediatric patients using high-
resolution imaging devices with concern about radiation exposure. In this context, a
truly hybrid imaging tool, such as simultaneous positron emission tomography/
magnetic resonance (PET/MR), presents the appealing advantage to combine serial
imaging technology (MR) and a volumetric (PET) method, at the same time under
the same conditions, to define and to assess a pathophysiological pattern for each
disease in every single patient aiming to customize therapeutic strategy, therefore
improving survival rate. Furthermore, a simultaneous approach enables to
M. Salvatore (*)
SDN Foundation, Institute of Diagnostic and Nuclear Development, Naples, Italy
e-mail: marsalva@unina.it
C. Nappi • A. Cuocolo
Department of Advanced Biomedical Sciences, University Federico II, Naples, Italy

DOI 10.1007/978-3-319-21371-2_2
20 M. Salvatore et al.
overcome some of the limitations of current PET/computed tomography (CT) scan,

such as misregistration of attenuation (CT) and emission (PET) images due to spa-
tial and temporal mismatch between CT and PET acquisitions, thus reducing arti-
factual false-positive result percentage. In addition, the possibility of matching two
powerful modalities such as MR and PET opens the way for new challenging clini-
cal applications for disease characterization that are currently under investigation,
e.g., multiorgan disorders. In this chapter we will focus on the potential clinical role
of PET/MR in pediatric diseases.
2.2 Available Diagnostic Tools in Pediatric Diseases
Nuclear medicine procedures are able to address several childhood diseases in

the manner of diagnosis, treatment planning, monitoring, and follow-up by using
well-established diagnostic methods. Thanks to advanced single-photon emis-
sion CT (SPECT) and PET systems available and state-of-the art CT and MR
devices combined with a wide range of radiopharmaceuticals and contrast agents
developed, most childhood-specific disorders can be accurately studied. In par-
ticular, radionuclide techniques with the use of gamma camera have been widely
validated and applied to investigate the kidney and urinary tract in children by
using three categories of 99mTc-labeled radiopharmaceuticals: diethylene tri-
amine pentaacetic acid for glomerular filtration rate measurement, mercaptoacet-
yltriglycine for tubular secretion assessment, and dimercaptosuccinic acid for
evaluation of tubular retention. Bone scintigraphy with 99mTc-methylene diphos-
phonate as specific tracer is a valuable tool for identification of alterations of
bone metabolism derived from benign or malignant pathologies. In addition, the
recent introduction of 18F-sodium fluoride as PET tracer allows the achievement
of higher-resolution images with similar dosimetry for pediatric bone malignan-
cies evaluation. Regarding to neuroimaging, brain tumors and epilepsy can be
investigated with MR and the support of SPECT or PET techniques by using
99m
Tc-ethyl cysteinate dimer, 99mTc-hexamethylpropylene amine oxime for
SPECT, and 18F-fluorodeoxyglucose (FDG) for PET. Other brain PET receptor
tracers have also been introduced, such as serotonin markers (5-HT1A, MPPF
(4-(2’-methoxyphenyl)-1-[2’-[N-(2”-pyridinyl)-pfluorobenzamido]ethyl]pipera-
zine), dopamine system receptors [18F]-fluoro-L-dopa, [18F]-fallypride), gluta-
mate/NMD receptors (11C-S-ketamine, 11C-CNS 5161), and opiate receptors
(11C-carfentanil). However some limitations, such as commercial availability,
restrict their use in clinical practice. As regards imaging in oncology, in the last
decades FDG-PET/CT has emerged as valuable method for metabolic character-
ization of hematologic and solid malignancies. Qualitative image evaluation
combined with standardized uptake value assessment is a validated approach for
staging, assessing response to therapy, and detecting disease recurrence. Novel
developed tracers, such as 11C-methionine and 18F-fluorothymidine for gliomas,
18
F-dihydroxyphenylalanine (DOPA), 68Ga-DOTANOC, and other analogues for
neuroendocrine tumor investigation, may increase the accuracy of method.
2 PET/MR in Children 21
2.3 PET/MR in Pediatric Patients
2.3.1 Neurological Disorders
2.3.1.1 Epilepsy
According to the last World Health Organization report (WHO fact sheet 999
October 2012), around 50 million people worldwide suffer from epilepsy. Therefore,
the estimated proportion of the general population with active epilepsy (i.e., con-
tinuing seizures or the need for treatment) is between 4 and 10 per 1000 people. The
most common type is idiopathic epilepsy with unknown etiology. Secondary epi-
lepsy is caused by brain damage from prenatal or perinatal injuries, congenital
abnormalities, or brain infections such as meningitis, encephalitis, or a brain tumor.
Children with medically intractable epilepsy can be considered as candidates for
surgery. However, the success of a surgical approach strongly depends on the pre-
cise presurgical identification of epileptogenic foci, for which MR is the most reli-
able tool [1–4] with T1 acquisition for imaging anatomy and various T2 sequence
acquisitions for detecting tissue pathology, such as fast low-angle inversion recov-
ery and gradient recalled echo. In addition, several details may be measured with
~1 mm of spatial resolution using a whole-brain T1- or T2-weighted MR scan, such
as local gray matter volume, cortical thickness, and sulcal depth. The integration of
provided information results in an extremely sensitive and specific tool (97 % and
83 %, respectively ) for a deep investigation of epilepsy. Nevertheless, a number of
patients with temporal lobe epilepsy do not show any suspected lesion on MR scans
(nonlesional epilepsy). In the pediatric population, this is a common occurrence
because of the higher frequency of cortical dysplasia [5] that often shows false-
negative on MR scans [6, 7].
FDG-PET has been shown to achieve high detectability regarding temporal lobe
epilepsy seizure focus, with a decreased glucose uptake in the epileptogenic tempo-
ral lobe [8], and better surgical prognosis has been reported in cases with FDG-PET
hypometabolism. In addition interictal PET with FDG can identify those brain mal-
formations of cortical development that are invisible to MR but are confirmed his-
tologically post-operation [9, 10]. Therefore, PET may have a clinical role in
pediatric epilepsy practice [11], revealing abnormalities otherwise difficult to
detect. PET sensitivity may increase by using specific statistical analysis methods,
such as statistical parametric mapping, and by PET/MR co-registration. The ability
of PET/MR to delimit the anatomic boundaries of hypometabolic areas should be
noted, as this can help stereotactic neuronavigation-guided surgery [12]. The ana-
tomical definition of the hypometabolic area suggests PET/MR as a useful tool for
a complete and accurate resection. PET/MR as a pre-operatory modality has shown
the same accuracy of PEt alone in detecting hypometabolic areas in pediatric non-
lesional patients, showing a good concordance with electro-clinical data [12].
Postsurgical outcomes of patients supported the usefulness co-registered PET/MR
images in neuronavigation systems. Furthermore, especially in younger children,
the number of episodes and the length of sedation or anesthesia may be reduced
when the procedures are performed simultaneously [13].
2.3.1.2 Tuberous Sclerosis Complex

Tuberous sclerosis complex is an autonomic-dominant neurocutaneous syndrome
with multiorgan impairment. In the brain, subependymal giant-cell astrocytomas,
subependymal nodules, and tubers are characteristic findings. With an early onset at
infancy age, patients may develop intractable epilepsy in childhood due to single
tuber. Given the medically refractory nature of the epilepsy, surgery should be con-
sidered for such cases. An accurate preoperative assessment of the culprit tuber is
therefore necessary to guide a successful resection of the epileptogenic tuber. In this
context a multimodal approach with FDG-PET/MR may lead to a detailed presurgi-
cal evaluation using a diffusion-weighted MR approach supported by interictal
hypometabolism of FDG-PET in the region of detected tuber.
2.3.1.3 Brain Tumors

Central nervous system tumors are the most frequent solid neoplasm in children
[14–16] accounting for 20 % of all malignancies [17] and for the majority of pedi-
atric cancer deaths [18]. Among these, benign gliomas, primitive neuroectodermal
tumors, and craniopharyngiomas account for the majority of brain tumors in chil-
dren. Therefore, there is great interest in advanced imaging modalities for diagno-
sis, staging, and treatment monitoring of brain tumors in the pediatric population.
In the evaluation of central nervous system tumors, MR imaging with high soft-
tissue resolution, multiplanar capability, and lack of ionizing radiation allows the
determination of tumor size, location, and its characterization, but its use is limited
in tumor physiology assessment and demonstration of tumor progression and recur-
rence. Contrast enhancement with MR imaging, a common finding in high-grade
tumors, could be related to surgery and/or radiation therapy, thus misleading patient
follow-up. On the contrary, PET can provide quantitative assessment of functional
and metabolic changes of the tumor tissue providing additional information to esti-
mate tumor proliferative activity. A large variety of protocols including dynamic
contrast-enhanced imaging, diffusion imaging, functional MR imaging, T1 perme-
ability, and MR spectroscopy coupled with the exceptionally high sensitivity of
PET in the picomolar range allow PET/MR to provide anatomic, functional, and
quantitative information [19]. Therefore, combined PET/MR is expected to improve
diagnostic accuracy and to help guided biopsy, surgery, or radiation therapy plan-
ning through the precise localization of hypermetabolic, vital tumor tissue and the
accurate definition of the target volume. Furthermore, the simultaneous acquisition
of PET and MR data provides precise information about tumor biology and the
tumor response after antitumor therapy [13].
FDG-PET is very sensitive in detecting poorly differentiated tumors such as
high-grade gliomas and cerebral lymphoma. On the other side, PET imaging can be
confounded by the high uptake normally seen in the cortex, resulting in less accu-
rate detection of low-grade gliomas [20]. However, a variety of non-FDG-PET trac-
ers with oncological brain applications have been developed. 11C-methionine,
O-(2-18F-fluoroethyl)-L-tyrosine, and 18F-DOPA have higher accuracies compared
with FDG for the detection of low- and high-grade gliomas and for assessment of
the treatment response because of better tumor-to-nontumor ratio [21–24].
PET with methionine has been documented for the first time to be capable of
diagnosing brain tumors that are histologically and/or anatomically characteristic in
children and substantially different from the predominantly astrocytic tumors previ-
ously studied in adults. The intensity of amino acid uptake can be assessed reliably,
even by qualitative inspection of the image, and appears to reflect the histological
grade and malignancy of tumors [25].
2.3.2 Oncological and Hematological Disorders
2.3.2.1 Lymphoma
PET/CT imaging is well established as a valuable tool in pediatric oncology for
diagnosis and follow-up. The greater value offered by MR compared to CT for
pediatric oncologic studies due to high soft-tissue resolution [26] combined with
reduced radiation exposure encouraged the introduction of PET/MR in children.
Non-Hodgkin and Hodgkin lymphomas account for about 10 and 18 % of all pedi-
atric tumors. Malignant lymphomas are staged using the Ann Arbor staging system,
except for childhood non-Hodgkin lymphomas that are staged using the Murphy
staging system [27, 28]. The use of FDG-PET for staging and treatment planning
has been widely validated [29] above all for Hodgkin and high-grade non-Hodgkin
lymphomas with sensitivity of 95 % and specificity of 99 % [30]. In addition, PET
imaging shows great value in evaluation of response to therapy monitoring, allow-
ing residual mass characterization as fibrosis or active disease [29]. On the other
hand, whole-body MR imaging techniques and particularly whole-body diffusion-
weighted imaging may be a good radiation-free alternative to CT with high sensitiv-
ity for the detection of lesions with a sensitivity of about 96 %. This method provides
anatomical information about tumor site and tissue characterization and correctly
identifies the biopsy site, essential for diagnosis and treatment planning. In addition,
short TI inversion recovery approach allows detection of parenchyma and bone
marrow lesions that show high signal intensity. The major weakness of MR imaging
is its low specificity for evaluation of post-therapeutic changes due to persisting
bone marrow edema, necrotic tissue, and contrast enhancement in successfully
treated lesions especially in children with variations of bone marrow appearance
related to age leading to misinterpretation [31]. The visualization of both nonmalig-
nant and malignant lymph nodes has been described as another important limitation
of functional MR diffusion-weighted imaging method. A combined approach by
using hybrid PET/MR may overcome most limitations of these two modalities
alone. For example, given that for the differentiation between a mediastinal mass
and physiological thymic or increased post-therapeutic uptake the use of PET imag-
ing alone in children reveals lower accuracy [32], PET/MR might better differenti-
ate from recurrent lymphoma or thymic rebound.
2.3.2.2 Histiocytosis
Langerhans cell histiocytosis identifies a small group of disorders involving clonal
proliferation of activated dendritic cells and macrophages [33]. This disease usually
affects children between the age of 1 and 15 years. Typically involved are bone,
lung, skin, and lymph nodes, but during the course of the disease any organ system
may be affected [34]. Prognosis is determined by the involvement of organs at risk
(liver, spleen, hematopoietic system) and response to treatment. Whole-body imag-
ing is the first choice approach for evaluation of active disease [35, 36]. PET and
MR imaging have been demonstrated to be powerful tools in multifocal disease
detection [37]. FDG-PET imaging for evaluation of pediatric patients with
Langerhans cell histiocytosis has been widely validated. Indeed FDG-PET shows
high sensitivity and specificity in lesion detection and high accuracy in monitoring
chemotherapy response earlier than other imaging modalities [38, 39].
MR imaging has become an integral part of Langerhans cell histiocytosis staging
[40] due to high spatial resolution and good soft-tissue contrast that allow biopsy
planning in complex anatomic sites. MR has shown great value in identification of
bone marrow involvement or soft-tissue masses in this disorder [41]. Bone lytic
lesions are isointense to muscle on T1-weighted MR images, and signal hyper-
intensity on T2-weighted images may detect the presence of perilesional edema.
These findings combined with contrast enhancement assessment are correlated with
lesion activity. MR is also the leading imaging modality in brain Langerhans cell
histiocytosis lesion identification, while FDG uptake of the cerebral cortex and sub-
cortical nuclei most likely interfere with uptake patterns of the intracerebral infil-
trates and could lead to false-negative results. Therefore, a hybrid PET/MR approach
may result in a complementary and powerful tool, becoming the first choice for
initial evaluation of patients with Langerhans cell histiocytosis with reduction of
examination time, sedation, and radiation exposure and high diagnostic accuracy.
2.3.2.3 Neuroblastoma
According to the American Cancer Society, neuroblastoma is by far the most com-
mon and often lethal cancer in infants (less than 1 year old) and accounts for about
7 % of all cancers in children. Adrenal glands are the most common site of disease.
Tumor resection is the mainstay of treatment for localized disease. However, in
most cases the disease has already spread to bone marrow when it is diagnosed.
Anatomic imaging tools, such as CT and MR are used to evaluate the extension of
primary tumor and involved lymph nodes. On the other hand,
123
I-metaiodobenzylguanidine (MIBG) imaging, bone scintigraphy with methylene
diphosphonate, and FDG-PET/CT evaluate the whole-body spread of disease.
While MIBG is the first-line functional imaging modality with specificity and sen-
sitivity of 83–92 % and 88–93 %, respectively, the use of FDG-PET/CT is still
under evaluation. However, it is suggested for delineation of suspected findings at
MR with little or no MIBG avidity and whenever there is any discrepancy between
MIBG scan and other modalities results. Moreover, other specific tracers are cur-
rently under investigation for PET sympathetic imaging, such as
11
C-hydroxyephedrine, 11C-epinephrine, 18F-fluorodopamine, and 18F- DOPA. Other
non-FDG-PET tracers, such as 68Ga- and 177Lu-octreotide, have been recently sug-
gested to detect somatostatine receptor-positive lesions with a potential role for tar-
geted radiotherapy. A combined PET/MR approach may be suggested to optimize
the study of morphological findings with functional and metabolic information in

one examination.
2.3.3 Cardiac Disorders
A hybrid PET/MR approach is also promising in pediatric population for early

detection of cardiovascular impairment of metabolic disorders. The appealing
advantage to combine cardiac function and morphology information with a serial
imaging technology (MR) and a volumetric (PET) method, at the same time under
the same cardiac conditions, may succeed in improving a long-term survival in this
category of patients. The evaluation of myocardial mass, anatomy, and cardiac
chamber volume as well as myocardial perfusion and scar can be detected by MR
imaging by assessing alteration of early and late gadolinium enhancement after con-
trast agent administration. On the other hand, cardiac PET with FDG gives accurate
information about myocardial metabolism and tissue viability. A hybrid PET/MR
device enables to complementary assess anatomy, function, metabolism, and wall
motion, overcoming some limitations of current PET/CT scan, such as misregistra-
tion of attenuation (CT) and emission (PET) images due to spatial and temporal
mismatch between CT and PET acquisitions yielding artifactual false-positive
results. The study of congenital heart disease and metabolic disorder with cardiac
involvement may therefore benefit this tool. However, the great potential of PET/
MR in this field is still under investigation.
2.3.4 Fever and Inflammation of Unknown Origin
Fever and inflammation of unknown origin are challenging fields in adult and pedi-
atric patients. Inflammatory diseases, such as rheumatic and autoimmune disorders,
systemic diseases, infections, and neoplasm are usually responsible of these condi-
tions. Although there is no agreement about the most valuable approach to investi-
gate patients with fever or inflammation of unknown origin, an early detection and
precise localization of the primary focus are necessary to lead further diagnostic and
therapeutic procedures [42]. FDG-PET/CT shows high sensitivity for the diagnosis
of fever and inflammation of unknown origin, but its role is still under investigation
[43]. In pediatric population, FDG-PET/CT may provide additional information in
children with pneumonia, disseminated candidiasis, cytomegalovirus spleen infec-
tion, vasculitis (e.g., in the context of Henoch-Schönlein purpura or Kawasaki dis-
ease), musculoskeletal inflammation, and inflammatory bowel disease [44].
Regarding inflammatory bowel disease in children and adolescents, FDG-PET is
able to evaluate the extent and degree of inflammation, in particular in parts of the
small bowel that are inaccessible to endoscopy. On the MR side, diffusion-weighted
imaging could improve the detection of Crhon’s-affected small-bowel segments,
and apparent diffusion coefficient values may also be helpful for assessing the
degree of inflammation distinguishing fibrotic and inflammatory bowel strictures.
The approach of combined PET/MR with various MR techniques may be beneficial

for the accurate detection and monitoring of disease activity with main advantages
for the investigation of soft tissues, vascular structures, and cardiac chambers, usu-
ally involved in infections. However, the use of FDG as tracer may lead to a high
number of false-positives. Therefore, more specific radiopharmaceuticals should be
considered as an alternative.
Conclusions
The opportunity to combine PET functional imaging with an accurate ana-
tomic imaging tool such as MR in a single hybrid device offers the great chance
to enhance the available diagnostic capabilities without additional radiation
compared to PET/CT scan. This is of particular relevance in pediatric patients
needing multiple scans during follow-up. A truly hybrid imaging approach,
such as simultaneous PET/MR, presents the appealing advantage to combine
serial imaging technology (MR) and a volumetric (PET) method, at the same
time under the same conditions, to define and to assess a pathophysiological
pattern for each disease in every single patient aiming to customize therapeutic
strategy, therefore improving survival rate. Furthermore, a simultaneous
approach enables to overcome some limitations of current PET/CT scan, such
as misregistration of attenuation (CT) and emission (PET) images due to spa-
tial and temporal mismatch between CT and PET acquisitions, thus reducing
artifactual false-positive result percentage. In addition, the possibility of
matching two powerful modalities such as MR and PET opens the way for new
challenging clinical applications for disease characterization that are currently
under investigation, e.g., multiorgan disorders. Despite of the great potential of
this novel approach, some limitations still weaken its routine use. Claustrophobia
and indwelling metallic devices such as defibrillators and pacemakers are gen-
eral limitations of this approach as well. Regarding pediatric population, pri-
vate coverage across pediatrics is currently limited. Therefore, reimbursement
is another challenging question. The difficult spread of PET/MR devices, due
to high costs, still limits a routine use in the clinical and research field.
Additionally, a new generation of well-trained specialists with expertise in
both modalities is required to guarantee a multidisciplinary team for image
interpretation.
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Current Issues in Molecular
Radiotherapy in Children 3
Mark N. Gaze, Jennifer E. Gains, and Jamshed B. Bomanji
Contents
3.1 Molecular Radiotherapy 29
3.2 The Care of Children with Cancer 31
3.3 Staffing and Facilities for Molecular Radiotherapy in Children 32
3.4 Radiation Protection 34
3.5 Thyroid Cancer 35
3.6 Neuroblastoma 38
3.7 Neuroendocrine Cancers 43
3.8 Forward Look 46
References 47
3.1 Molecular Radiotherapy
Molecular radiotherapy, sometimes also called radionuclide therapy or biologically

targeted radiotherapy, is the treatment of cancer using systemically administered
radiopharmaceuticals.
In essence, molecular radiotherapy involves the use of a radiolabelled carrier
molecule. The vector is physiologically concentrated and retained by tumour
tissues, as predicted by imaging biomarker studies, to a much greater extent
than by nontarget tissues. As radioactive decay occurs, the targeted cancer cell
is irradiated and receives potentially lethal damage to its DNA. When that cell
M.N. Gaze (*) • J.E. Gains

Department of Oncology, University College London Hospitals NHS Foundation Trust,
250 Euston Road, London NW1 2PG, UK
e-mail: mark.gaze@uclh.nhs.uk; jenny.gains@uclh.nhs.uk
J.B. Bomanji
Department of Nuclear Medicine, University College London Hospitals NHS Foundation
Trust, 235 Euston Road, London NW1 2BU, UK
e-mail: jamshed.bomanji@uclh.nhs.uk

DOI 10.1007/978-3-319-21371-2_3
30 M.N. Gaze et al.
subsequently attempts mitosis, it fails to replicate and undergoes apoptosis.

Depending on the path length of the emitted radiation, neighbouring cells,
which may not have taken up the radiopharmaceutical, may be lethally injured
by crossfire. Cytokines released by damaged or dying cells may induce apopto-
sis in adjacent cells. These are called the physical and biological bystander
effects [31, 13]. These mechanisms enable molecular radiotherapy to be effec-
tive, even when there is heterogeneity of uptake of the radiopharmaceutical
within the tumour [30].
Radiopharmaceuticals for molecular radiotherapy range from very simple to
more complex. For example, 131I-sodium iodide (131I-NaI) is merely a radioactive
salt, which may be taken orally. Once in the systemic circulation, it is taken up by
the sodium iodide symporter molecule, expressed in benign and malignant thyroid
cells, and also to some extent in salivary gland, stomach and breast tissue [4]. More
complex examples are somatostatin analogues linked to a radio-metal such as 90Y or
177
Lu via 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetra-acetic acid (DOTA), a che-
lating molecule, for peptide receptor radionuclide therapy (PRRT). These include
[90Y-DOTA]-Tyr3-octreotide (90Y-DOTATOC) [22] and [177Lu-DOTA]-Tyr3-
octreotate (177Lu-DOTATATE) [5].
While molecular radiotherapy is conceptually straightforward, it can be a
challenging treatment to deliver safely, requiring multi-professional input from
physicists, nurses, radiographers, pharmacists and medical practitioners from a
range of disciplines including oncology and nuclear medicine. Inevitably the
use of molecular radiotherapy exposes the patient to ionising radiation which
may have adverse as well as beneficial effects, and its delivery is made more
difficult by the need for optimal radiation protection facilities and procedures
to minimise exposure to healthcare professionals, family members and the
public.
The field of molecular radiotherapy is moving forward as a result of the devel-
opment of new radiopharmaceuticals and imaging technology. There is a growing
understanding of the science underlying the effectiveness and limitations of
molecular radiotherapy. As its integration with other cancer treatment modalities
allows it to be used in potentially curative, rather than simply palliative, treatment
strategies, there is an increasing need for careful dosimetry in relation to both
tumour deposits and normal tissues, as this may be dose-limiting. As a general
principle, all forms of radiotherapy seek to maximise the delivery of radiation to
cancer cells while minimising the radiation exposure of healthy normal tissues.
This will increase the therapeutic ratio, thereby maximising the effectiveness of
the therapy and minimising unwanted side effects. Molecular radiotherapy is no
exception to this, and so if outcomes are to be improved, target and normal tissue
dosimetry must become the standard of care, as it is for external beam
radiotherapy.
The British Institute of Radiology has published a report on the current status of
molecular radiotherapy in the UK, with recommendations for further investigation
which gives valuable information for the reader wishing to know more about molec-
ular radiotherapy in general [3].
3 Current Issues in Molecular Radiotherapy in Children 31
3.2 The Care of Children with Cancer
Cancer in children is rare, with only about 1,500 cases per year occurring in chil-
dren up to 15 years of age in countries the size of France, Italy and the UK. Many
different types are encountered, each of which is even less common. Each type
requires individualised specialist multidisciplinary care, by teams which have expe-
rience and expertise. So for best outcomes it is accepted that coordination of care
should be centralised at a recognised principal treatment centre for children and
young people with cancer, although aspects of care may be undertaken closer to
home at a paediatric oncology shared care unit. [29].
In each principal treatment centre there will be regular, paediatric oncology mul-
tidisciplinary team meetings for the subtypes of children’s cancer. At these, the
clinical presentation, imaging and pathology will be reviewed to confirm the diag-
nosis and to assign a stage and risk classification. The various treatment options,
including clinical trials, will be considered and the most suitable one chosen. The
course of the patient through treatment, including response assessment, will be
monitored. In the event of unexpected toxicity, poor response or disease progres-
sion, alternative treatments will be considered. It is important that a clinician expe-
rienced in the indications for molecular radiotherapy is present at these meetings, so
that it is not forgotten as an option in suitable cases.
There is a recognised national standard for the care of children, the National
Service Framework for Children, Young People and Maternity Services, and this
include the following recommendations [6]:
• Children and young people and families should receive high-quality services,
which are coordinated around their individual and family needs, and take into
account their views.
• All children and young people who are ill will have timely access to appropriate
advice and to effective services, which address their health, social, educational
and emotional needs throughout the period of their illness.
• Children and young people should receive high-quality, evidence-based hospital
care, developed through clinical governance and delivered in appropriate
settings.
• Children who have complex health needs should receive coordinated, high-
quality child- and family-centred services, which are based on assessed needs,
which promote social inclusion and, where possible, which enable them and
their families to live ordinary lives.
• Children, young people, their parents or carers and healthcare professionals in all
settings make decisions about medicines based on sound information about risk
and benefit. They have access to safe and effective medicines that are prescribed
on the basis of the best available evidence.
Other recommendations pertinent to children receiving molecular radiotherapy

come from Improving Outcomes in Children and Young People with Cancer [29].
This guidance includes the following:
32 M.N. Gaze et al.
• Children and young people should receive age-appropriate safe and effective
services as locally as possible, not local services as safely as possible.
• All aspects of care for children and young people with cancer should be under-
taken by appropriately trained staff.
• All care for children and young people under 19 years old must be provided in
age-appropriate facilities.
• All children and young people must have access to tumour-specific or treatment-
specific clinical expertise as required.
• For some conditions, radiotherapy is high risk, very complex or requires special-
ised equipment, and it should be commissioned from agreed supraregional,
national or international centres. Such radiotherapy specifically includes molec-
ular radiotherapy treatment.
Taking into account the rarity and diversity of malignant disease in children, and
the requirements for specialist care, the number of principle treatment centres for
children and young people with cancer is limited. There are 20 such centres in the
UK and Republic of Ireland, 18 of which deliver external beam radiotherapy.
However the added complexities of molecular radiotherapy are such that very few
of these principal treatment centres are able to deliver this treatment.
3.3 Staffing and Facilities for Molecular Radiotherapy

in Children
Given the potential complexity of molecular radiotherapy and the requirements for
dosimetry (Sect. 3.1) and the particular requirements for the care of children with
cancer (Sect. 3.2), it is clear that molecular radiotherapy for children should be
delivered only in a relatively small number of appropriately staffed and equipped
supraregional centres. The Good Practice Guide for Paediatric Radiotherapy sets
out the requirements for such a centre, including the following [33]:
• Paediatric molecular radiotherapy should only be given in hospitals where there

are suitable protected facilities for the administration of treatment and subse-
quent care in a paediatric environment with round the clock paediatric medical
and nursing support.
• The team should include experienced paediatric clinical oncologists, therapeutic
radiographers with special expertise, play specialists, physicists for radiation
protection and dosimetry.
• General childcare is delegated to designated comforters and carers who require
space outside, but immediately adjacent to the protected room to wait and sleep.
• There needs to be on-site nuclear medicine imaging for dosimetry, with facilities
to perform scans under general anaesthetic if necessary.
The inpatient facilities for the administration of molecular radiotherapy to chil-

dren should be located on a paediatric oncology ward, to make it easy for
appropriately trained children’s doctors and nurses to care for the patient. The
radiation-protected treatment room should be a single bedroom, ideally light and
airy, with a cot or bed for the patient and with en suite toilet and shower facilities.
There should be a shielded door with a window to the ante-room, off which accom-
modation for parents is ideally situated. There should be a separate protected door to
the main ward. The advantage of having two protected doors is that when the radio-
active patient is in the bedroom, one of the two doors may be open and the other shut.
This will prevent other children on the ward from inadvertently entering the treat-
ment room, but allow the other door to be open to reduce the sense of isolation and
enclosure felt by the patient and carer. A separate service area for decontamination
of laundry and maceration of radioactive nappies before disposal in the sewerage
system is useful. As high activities of radioactive waste require disposal, sewage
retention tanks, which allow radioactive waste to decay before discharge into the
public sewerage system, may be useful to prevent discharge limits being exceeded.
In addition to space adjacent to the treatment room for comforters and carers, it
is ideal to have nearby hostel accommodation for family members, so that they can
take it in turns to act as carers and have a base to return to, to shower, rest, eat and
change clothes.
Nuclear medicine facilities require planar scintigraphy with SPECT and SPECT/
CT as a minimum requirement. The availability of PET/CT and ideally PET/MRI is
recommended. For whole-body dosimetry, an in-room ceiling-mounted radiation
detector is needed.
Play specialists perhaps deserve special mention. Although they are usually
found in children’s hospitals, they are less commonly seen in non-paediatric hospi-
tals and nuclear medicine departments. The qualified and registered hospital play
specialist plays a very important part in preparing children for molecular radio-
therapy, acting as a facilitator of communication through play.
The play specialist will help to inform the child or young person of what will be
happening, taking into account their age and development. Preparation can help to
reduce their anxiety and fear of the unknown and reduce any misconceptions they
may hold. Preparation by play specialists will also help the younger child to lie still
for diagnostic imaging and dosimetry scans, thereby reducing the need for general
anaesthesia. Their involvement will also help to ensure a personalised programme
of activities to reduce the risk of boredom while the child is confined to the treat-
ment room.
Coordination of treatments including liaison with referring clinicians and
community services; booking of diagnostic and dosimetric scans; scheduling of
treatment and ensuring the ordering of the radiopharmaceutical; information
giving to families and children, including teaching them about radiation protec-
tion procedures and regulations; recording radiation measurements; and risk
assessment for discharge planning requires a trained and dedicated individual,
ideally a specialist radiographer or clinical nurse specialist. He or she also has
a role in training paediatric medical and nursing staff, who often rotate fre-
quently and who may have limited knowledge and an intrinsic fear of radiation
in relation to their personal safety.
34 M.N. Gaze et al.
Adequate provision of radiation physics expertise is essential for radiation pro-

tection, and dosimetry, as well as for the more routine tasks of calibration and main-
tenance of equipment. Good radiopharmacy services are needed for the preparation,
quality assurance and dispensing of treatments. A Qualified Person may be required
to oversee the release of Investigational Medicinal Products in clinical trials.
3.4 Radiation Protection
Adults are typically well and self-caring, but babies and young children need sig-
nificant personal care and emotional support from adults. Radioactive patients and
radioactive bodily products represent a potential radiation hazard to adults looking
after children receiving molecular radiotherapy.
Radiation exposure is governed by laws, which vary by country. In the UK, these
are the Ionising Radiation Regulations 1999 (IRR99), derived from the European
Union’s Basic Safety Standards Directive 1996 96/29 as supplemented by the EU
Medical Exposure Directive 1997 97/43. This legislation requires that all radiation
exposures are justified and optimised to a level, which is ‘as low as reasonably
achievable’ (the ALARA principle).
Healthcare professionals are essential if radioactive patients require specific
medical or nursing interventions, and they will inevitably be exposed to some radia-
tion. As staff may look after many patients, in keeping with the ALARA principle,
it is essential that they do not receive any avoidable radiation exposure. Normal
childcare tasks such as feeding, washing, dressing, comforting and entertainment
are therefore delegated to other responsible adults during molecular radiotherapy.
These are called comforters and carers and are usually family members, most
often parents, who must not be pregnant. ‘Comforters and carers’ are defined by UK
IRR99 as individuals ‘knowingly and willingly helping (other than as part of their
occupation) in the support and comfort of patients undergoing medical diagnosis or
treatment’.
Comforters and carers are not subject to a specific cumulative dose limit, although
exposure is governed by the ALARA principle. Use of flexible dose constraints of
5 mSv per episode, or a dose constraint rather than dose limits, has been recom-
mended [16], suggesting. Higher doses may well be appropriate for parents of very
sick children. These recommendations are endorsed in the UK [14].
In order to be designated as a comforter and carer for a child undergoing a medi-
cal exposure to radiation, it is necessary for that individual to be fully informed of
the fact that he or she will be exposed to radiation and given clear expectation of the
risk of harm this may cause.
Individuals are taught how to minimise their personal radiation exposure. This
involves both avoidance of direct contamination by contact with radioactive materi-
als and minimising exposure to the radiation emanating from the patient. Disposable
plastic gloves, aprons and overshoes are used to reduce the risk of direct contamina-
tion by patient excreta – in the form of vomit, urine, sweat or faeces. They are
advised to minimise the time spent in close contact with the child they are giving
care to, to maximise the distance between themselves and the child when close
contact is not necessary and to use mobile, shielded protection screens where pos-
sible. If the individual agrees to be a comforter and carer, written consent is then
required.
The medical use of radioactive substances can arouse anxiety in people who may
misunderstand and overestimate the associated risks. This fear of radiation may
affect both the relatives of patients and even hospital staff who have been trained in
radiation protection. However the actual radiation exposure to comforters and carers
is not as great as some might fear.
There are limited data in the literature on comforter and carer doses during pae-
diatric molecular radiotherapy. With regard to 131I-mIBG therapy, there have been
four published papers on parental exposures relating to one, three, 13 and 62 patients
[10, 27, 36, 38].
The largest of these, a study reporting on 10 years of comforter and carer expo-
sure data for 131I-mIBG, 177Lu-DOTATATE and 131I-NaI showed that there were
higher comforter and carer doses for patients receiving 131I-mIBG therapy than
either 177Lu-DOTATATE or 131I-NaI, as significantly higher administered activities
of 131I-mIBG were used [10].
Although the administered activity in 131I-mIBG therapy patients was weight
based, and therefore increased with age as older patients were usually heavier, this
did not result in higher doses to comforters and carers as older patients required less
input and support. The highest comforter and carer doses were seen in the younger
patients.
The comforter and carer doses from the 177Lu-DOTATATE and 131I-NaI adminis-
trations were much lower and showed a range of doses received for the same fixed
administered activity.
3.5 Thyroid Cancer
Thyroid cancer is not common in children; only about ten patients under the age of
15 are registered annually in the UK [28]. Differentiated thyroid cancer of follicular
cell origin, including papillary and follicular variants, is the most common type. It
is often more advanced at presentation in children and young people, with a greater
incidence of nodal and distant metastases that is seen in adults, yet the long-term
survival figures are better, approaching 100 %.
The management of thyroid cancer is evolving. There are recent guidelines from
the British Thyroid Association for the management of adults, which incorporate
changes based on emerging evidence [32]. The published guidelines for the man-
agement of children [34] are older, and these are currently in the process of being
updated.
After cytological or pathological confirmation that a thyroid gland nodule or
cervical lymph node is malignant, the initial treatment is surgical. Ultrasound is the
best investigation to assess the extent of disease in the neck. If CT is indicated, only
non-contrast studies should be performed as iodine-containing contrast media may
36 M.N. Gaze et al.
affect the subsequent uptake of radioactive iodine for a period of 3 months. A total
thyroidectomy is performed, carefully preserving parathyroid glands and the func-
tion of the recurrent laryngeal nerves, together with removal of as many lymph
nodes shown on preoperative assessment to be involved as possible, but a formal
block dissection of the neck is not indicated. In cases of diagnostic doubt, a diagnos-
tic hemi-thyroidectomy may be performed, followed by completion thyroidectomy
if a significant cancer is demonstrated. Following surgery, patients are commenced
on thyroid hormone replacement therapy, usually with liothyronine at a dose of 20
micrograms three times a day, if thyroid hormone withdrawal is to be used prior to
radioactive iodine administration. This is the normal adult dose, and younger chil-
dren may need this to be scaled down.
It is standard practice to recommend radioactive iodine-131 ablation in all
patients except those with incidental micro-carcinomas less than 1 cm in diameter
without adverse features such as lymph node involvement or lympho-vascular
invasion.
Typically, fixed administered activities are used, the same for children as in
adults. For adult patients with low-risk disease, there is evidence that an adminis-
tered activity of just 1.1 GBq gives as good outcomes as a higher activity [21]. For
patients with adverse features such as nodal involvement or lympho-vascular inva-
sion, a higher activity of 3.0 GBq is often recommended. Most children and young
people with thyroid cancer are teenagers and can swallow a capsule. Liquid prepara-
tions of radioactive iodine are available for younger children and others challenged
by the thought of swallowing a capsule, although care must be taken, as it is easier
to get radioactive contamination with a liquid. It is also possible to administer the
liquid preparation via a nasogastric or percutaneous endoscopic gastrostomy (PEG)
feeding tube if necessary.
To promote uptake into thyroid cells, radioactive iodine should be given when
the thyroid stimulating hormone (TSH) levels are elevated (ideally > 30 mU/L). This
can be achieved either by thyroid hormone withdrawal (the traditional method) or
by administration of recombinant human TSH (rhTSH), which is now being used
more often than before. If, as usual, patients are on liothyronine, 10 days withdrawal
is adequate. If patients are on levothyroxine sodium, they should be changed to
liothyronine 28 days before the proposed administration of radioactive iodine, and
the liothyronine should then be stopped 10 days in advance. The main problem
patients experience with this is profound tiredness. If rhTSH, thyrotropin alfa (mar-
keted under the trade name of Thyrogen), is chosen (although its use in children is
unlicensed), there is no need for thyroid hormone withdrawal. Two deep intramus-
cular injections of 0.9 mg into the gluteal region are given 48 and 24 h prior to
radioactive iodine administration. Just prior to administration, blood should be
taken to document the TSH, stimulated thyroglobulin and thyroid hormone levels.
It should be noted that sometimes a rise in creatinine is observed which may be
flagged as acute kidney injury.
After administration, typically after 2 or 3 days, a scan should be performed to
demonstrate the localisation of the radioactive iodine in the body. This should be
whole-body planar scintigraphy and SPECT/CT of the neck. This will usually show
Fig. 3.1 Anterior (left) and posterior (right) planar scintigraphy of a child with papillary thyroid
carcinoma performed 72 h after treatment with 3.0 GBq 131I-sodium iodide. Uptake in the left side
of the thyroid bed and in multiple bilateral pulmonary metastases can be seen clearly, as well as
physiological uptake and excreted activity in the bowel and bladder
uptake in the thyroid bed and possibly separate nodal uptake in the neck. Sometimes
distant metastases, typically in the lungs, rarely in bone, may be shown (Fig. 3.1).
Care must be taken in interpretation of imaging, as artefacts may be caused by con-
tamination with saliva, sweat or urine on skin, clothing or toys. If unexpected find-
ings are seen, the patient may be re-scanned after a shower, wearing clean clothes.
The use of SPECT/CT helps to resolve many of the uncertainties over localisation
of uptake seen on planar scans, particularly whether abnormalities are within or
external to the body.
If thyroid hormone withdrawal was used, liothyronine treatment should be
recommenced on discharge from hospital.
Following ablation in a low-risk patient with only thyroid bed uptake, reassess-
ment with an iodine-123 whole-body survey and SPECT/CT may be performed
after a 6-month interval. If no uptake is seen and the stimulated thyroglobulin is
normal, the patient is in complete remission and can be followed up clinically and
with thyroid function and thyroglobulin blood tests. If residual uptake is
38 M.N. Gaze et al.
demonstrated, further treatment is indicated. The use of neck ultrasound and stimu-
lated thyroglobulin measurement 9–12 months after ablation is replacing the use of
iodine-123 scintigraphy in low-risk patients, except where the presence of antibod-
ies makes assessment of the thyroglobulin level difficult.
In high-risk patients, especially if nodal disease or distant deposits were identi-
fied on post-ablation imaging, further therapeutic administrations of radioactive
iodine are indicated. Typically 5.5 GBq is given after a 4–6 monthly interval. With
extensive disease, repeated administrations are usually recommended until no
uptake is seen, and the stimulated thyroglobulin is normal.
Following completion of treatment, patients should be switched from liothy-
ronine to levothyroxine sodium (unless they are already taking that) at slightly
supra-physiological doses with the aim of keeping the TSH suppressed. Dynamic
risk stratification can be used to guide the extent and duration of TSH suppres-
sion. Surveillance is based on clinical examination, supplemented if necessary
by ultrasound, and thyroglobulin measurement. Sometimes interpretation of thy-
roglobulin levels can be complicated by the presence of anti-thyroglobulin anti-
bodies, which may result in spuriously elevated or normal levels, depending on
the assay technique used. The anti-thyroglobulin antibody titre should therefore
be measured, and the result of other tests taken into account when trying to
assess the significance of the thyroglobulin level. Nuclear medicine imaging is
not routine unless there is a clinical suspicion. If the thyroglobulin is rising and
123-iodine imaging is normal, 18 F-FDG PET/CT can be used to see if there is
iodine non-avid disease, although this is unusual. Newly discovered kinase
inhibitors may improve uptake of radioiodine and are under investigation for this
application.
In the event of metastatic or local relapse, discussion at an experienced MDT
meeting is required, but patients can almost always be salvaged with appropriate
treatment, which may include further surgery and radioactive iodine
administration.
3.6 Neuroblastoma
Neuroblastoma is cancer predominantly found in babies and young children, more

rarely in school age children, and exceptionally in teenagers and young adults. It is
risk-stratified on the basis of age, stage and molecular pathology into low-, interme-
diate- and high-risk groups. The prognosis of low- and intermediate-risk groups is
similarly good, although intermediate-risk patients require more intense treatments
to achieve good outcomes [9].
Most patients have high-risk disease and are treated on international protocols
including dose-dense platinum-based induction chemotherapy to achieve meta-
static remission, surgical excision of the primary tumour, consolidation with high-
dose (myeloablative) chemotherapy, external beam radiotherapy and minimal
residual disease treatment with differentiating agents and immunotherapy.
However, even with these very intense multimodality treatment protocols,
although perhaps about one third may become long-term disease-free survivors,
the majority either have poorly responding disease or relapse after achieving a
remission.
Refractory and relapsed high-risk neuroblastoma is a good model for molecular
radiotherapy; as there are several specific cellular targets for radiopharmaceuticals,
the disease is disseminated making local treatment alone inadequate, and it is often
relatively radiosensitive.
The most common type of molecular radiotherapy for neuroblastoma is
iodine-131 meta-iodobenzylguanidine (mIBG), sometimes referred to as
Iobenguane. 131I-mIBG, a noradrenaline analogue, is taken up into neuroblas-
toma cells, and other cells of neural crest origin, by a specific cell surface mole-
cule, the noradrenaline transporter, in an oxygen- and energy-dependent active
transport process. Over 90 % of patients have disease showing specific uptake of
123
I-mIBG, on diagnostic imaging for staging and response assessment [17]. As a
treatment, 131I-mIBG has been used clinically for around 30 years and has a vari-
able but good clinical activity with a mean response rate of 32 % [39] (Fig. 3.2).
Fig. 3.2 Anterior planar 123I-mIBG scintigraphy of a child performed before (left) and after (right)
131
I-mIBG therapy, showing a reduction in the size and intensity of the abdominal tumour and
metastatic lesions, indicating a partial response
40 M.N. Gaze et al.
Over time, the way in which 131I-mIBG therapy has been used has evolved. As the
principal dose-limiting toxicity is haematological, investigators have sought to
circumvent this by using bone marrow or more recently peripheral blood stem
cell support [11, 23]. The use of haemopoietic support allows escalation of
administered activity to be undertaken. As haematological toxicity is related to
the whole-body dose received, safe dose escalation can be facilitated by the use
of real-time whole-body dosimetry to permit a desired whole-body dose to be
delivered with reasonable accuracy. There has also been interest in incorporating
radiation sensitisers such as the camptothecin derivatives topotecan and irinote-
can [7, 11]. Attempts have been made to improve outcomes by bringing molecu-
lar radiotherapy forward in the disease trajectory, from the relapse setting to the
treatment of poor responders to induction chemotherapy, and even as the first line
of treatment.
Although 131I-mIBG has undoubted activity against metastatic neuroblastoma,
and it has been used in a range of clinical settings, its established benefit is essen-
tially palliative, to control disease and the symptoms it causes, and perhaps to
prolong life. Its role as part of potentially curative strategies remains unclear and
is the subject of continuing clinical investigation. To date, no published ran-
domised trials have been shown in a recent systematic review (Wilson et al. 2014).
These are required to demonstrate superiority over other possible treatment
approaches.
Practical points in the use of 131I-mIBG therapy include the need to ensure that
patients are not taking concomitant medication which may interfere with uptake;
the long list of such drugs can be found in the EANM guidelines [12]. As free
iodine, formed by the radiolysis of 131I-mIBG, can be taken up by the thyroid, thy-
roid blockade is indicated. Various preparations can be used including potassium
iodide, potassium iodate, potassium perchlorate and Lugol’s iodine. Despite this,
there is still a risk of hypothyroidism and even thyroid cancer in long-term survi-
vors. To avoid nausea and vomiting, anti-emetic prophylaxis should be used. There
is a possibility that 131I-mIBG therapy can be associated with transient fluctuations
in blood pressure, so blood pressure must be controlled before and monitored dur-
ing and after treatment. [19, 40]
While the elective use of 131I-mIBG therapy is perfectly reasonable, it is prefer-
able for patients to be enrolled in prospective clinical trials when possible. It is
only through the use of sequential, well-designed clinical studies that the real
place of this treatment in the management of children with neuroblastoma will be
clarified.
Other molecular radiotherapy treatments have been investigated for neuroblas-
toma, but these have not yet gone beyond early-phase clinical trials, so must still
be considered as experimental and should not be recommended as standard
treatment.
177
Lu-DOTATATE, which targets the somatostatin receptor, is recognised as a
standard treatment in metastatic adult neuroendocrine cancers. Its use in a small
number of patients has been reported, and further clinical studies are in progress
[8, 26] (Fig. 3.3a–c).
Immunotherapy with semi-synthetic monoclonal antibodies directed against the
disialoganglioside GD2 is now recognised as standard treatment [41], but although
the use of radiolabelled monoclonal antibodies has been investigated preclinically
[18] and clinically [20] for decades, it has not found a definite niche in the therapeu-
tic armamentarium.
Fig. 3.3 (a) 68Ga-DOTATATE PET/CT images of a child with metastatic neuroblastoma to map dis-
ease extent prior to therapy, showing nodal deposits in the left inguinal and iliac region and a bone
metastasis in the left distal femur. Axial CT image through pelvis (upper left), corresponding axial
PET image (upper right), corresponding fused PET/CT image (lower left) and anterior PET maximum
intensity projection image (lower right). (b) Anterior planar scintigraphy 24 h after the first adminis-
tration of 177Lu-DOTATATE therapy (left) and 24 h after the second administration of 177Lu-DOTATATE
therapy 2 months later (right), demonstrating an impressive response to the first course of treatment.
(c) Follow-up 68Ga-DOTATATE PET/CT images of the same child 6 weeks after the two
177
Lu-DOTATATE therapy administrations, showing complete response in the nodal deposits in the left
inguinal and iliac region and a partial response in the bone metastasis in the left distal femur. Axial CT
image through pelvis (upper left), corresponding axial PET image (upper right), corresponding fused
PET/CT image (lower left) and anterior PET maximum intensity projection image (lower right)
42 M.N. Gaze et al.
Fig. 3.3 (continued)

3.7 Neuroendocrine Cancers
Neuroendocrine tumours are a heterogeneous group of neoplasms which may arise

at a variety of sites including the gut, pancreas, lung, thyroid gland and sympathetic
nervous system. They vary also in their histological grade and malignant potential.
Included in this group are phaeochromocytoma, paraganglioma, medullary carci-
noma of the thyroid, carcinoid tumours, gastrinoma and more. While localised
tumours are often amenable to curative surgical resection, widely metastatic tumours
are incurable. Nevertheless they are very amenable to a range of treatments includ-
ing molecular radiotherapy. Mostly they occur in adults, and they are very rare in
children. They may be associated with a number of genetic predisposition syn-
dromes or be familial.
Diagnostic imaging with 123I-mIBG and 68Ga-DOTATATE (or 111In-Pentetreotide)
may show the extent of disease and indicate whether an attempt at molecular
radiotherapy with either 131I-mIBG or peptide receptor radionuclide therapy with,
for example, 177Lu-DOTATATE is merited. Patients with metastatic neuroendo-
crine cancers showing good uptake of both diagnostic tracers may receive both
treatments sequentially. Patients with metastatic neuroendocrine cancers of adult
type, unlike neuroblastoma, do not usually have widespread bone marrow infiltra-
tion and have often not been heavily pretreated with intensive chemotherapy. Sub-
myeloablative activities of 131I-mIBG therapy are therefore often well tolerated
without dangerous myelosuppression, and so collection of haemopoietic stem
cells in advance with planned reinfusion is not necessary (Fig. 3.4a–c). The main
potential toxicity of peptide receptor radionuclide therapy is renal impairment,
but 177Lu-DOTATATE is less toxic in this regard than 90Y-DOTATATOC, and the
use of an amino acid infusion will also significantly protect the kidneys. Expert
guidance on the use of peptide receptor radionuclide therapy has been published
by the EANM [1].
44 M.N. Gaze et al.
Fig. 3.4 (a) Anterior (left)

a
and posterior (right) planar
scintigraphy images of a
child with metastatic
paraganglioma after the first
administration of a
sub-myeloablative activity of
131
I-mIBG therapy,
indicating the extent of
disease prior to treatment.
(b) After the fourth
administration of 131I-mIBG
therapy approximately 6
months later, anterior (left)
and posterior (right) planar
scintigraphy demonstrate a
significant response to
therapy. (c) After the sixth
administration of 131I-mIBG
therapy approximately 10
months after the first,
anterior (left) and posterior
(right) planar scintigraphy
demonstrate a continuing
response to therapy
Fig. 3.4 (continued) b

46 M.N. Gaze et al.
Fig. 3.4 (continued) c
3.8 Forward Look
The foregoing sections have outlined what molecular radiotherapy is, some of the
specific challenges of using molecular radiotherapy in children compared with
adults and the principal current established uses of molecular radiotherapy in chil-
dren. However, no medical field stands still, and this area of endeavour will change
over time. Predicting future trends is always hazardous, but we think there will be a
gradual expansion of the indications for this type of treatment, driven by the better
understanding of new targets, development of novel targeting agents and advances
in radiochemistry leading to more therapeutic radionuclides becoming available.
As longer survival, and perhaps cure, becomes possible for more patients, pro-
tection of normal organs through careful dosimetry and dosimetrically planned
treatment will become more important [35]. Carrier free 131I-mIBG has been used in
early-phase clinical trials [24], but it is too soon to know whether it is better than
conventional 131I-mIBG prepared by iodide exchange, which has an excess of unla-
belled mIBG molecules which may compete with labelled ones for uptake into neu-
roblastoma cells. Alpha particle therapy does not yet have a place in paediatric
treatment, but there is growing adult use in metastatic prostate cancer [15], and
preclinical investigations in relation to neuroblastoma have been undertaken using
analogues of mIBG labelled with the alpha particle emitter 211At [37]. Labelled
monoclonal antibodies directed against bone marrow cells offer the potential for
reducing the use of total body irradiation as part of the conditioning for bone mar-
row transplantation [25]. Optimal integration of molecular radiotherapy with other
modalities including external beam radiotherapy and chemotherapy will be further
investigated [2].
Molecular radiotherapy is a leading example of personalised biomarker-stratified
precision medicine and should be at the forefront of clinical and basic research.
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Radiation Risk from Medical
Exposure in Children 4
Michael Lassmann and Uta Eberlein
Contents
4.1 Introduction 51
4.2 Risk Definitions 52
4.2.1 LNT Model: Linear No-Threshold Model 52
4.2.2 The Use of Effective Dose in Epidemiology 53
4.3 Data on Radiation Risk in Nuclear Medicine 54
4.3.1 Thyroid Cancer Caused by Diagnostic Exposure of I-131 54
4.3.2 Thyroid Cancer Caused by Radiation Exposure of the Japanese Atomic
Bomb and the Chernobyl Accident 56
4.3.3 Radiation Risk in Children 57
Conclusions 58
References 58
4.1 Introduction
Diagnostic nuclear medicine procedures imply the administration of activity levels

that do not lead to the appearance of radiation deterministic effects. Effects to be
expected, if at all, are stochastic effects of ionizing radiation. The assessment of
adverse health effects from exposure of ionizing radiation in the dose range com-
monly encountered in clinical (and pediatric) diagnostic nuclear medicine is based
on epidemiological and biological data. Most of the data on the effects on human
health after exposure to ionizing radiation comes from the Life Span Study of the
survivors of the bombings of Hiroshima and Nagasaki, as reported by the Radiation
Effects Research Foundation [18, 22–24]. In addition, there are few data on the
stochastic radiation risk after treatment of thyroid diseases with radioiodine [10, 21,
M. Lassmann (*) • U. Eberlein

Klinik und Poliklinik für Nuklearmedizin, Universitätsklinikum Würzburg,
Oberdürrbacher Str. 6, Würzburg D - 97080, Germany
e-mail: lassmann_m@ukw.de

DOI 10.1007/978-3-319-21371-2_4
52 M. Lassmann and U. Eberlein
26, 31]. However, there is no clear evidence that there is an increase in cancer risk
associated with I-131 therapy [31]. No such data are available concerning the poten-
tial cancer risk of diagnostic nuclear medicine.
For a risk assessment of medical diagnostic procedures involving ionizing radia-
tion, the concept of the effective dose has been widely adapted. The risk associated
with the effective dose is based on assumptions such as the concept of considering
the risk to the general public or to workers. This does not reflect the situation for
patients in nuclear medicine. Another aspect is the strong age and sex dependency
of the radiation risk, which is not included in the effective dose. Therefore, the
effective dose should not be used for risk-benefit assessments in patients; instead,
the relevant quantity is the equivalent dose or the absorbed dose to irradiated organs.
However, for comparing different medical procedures, effective dose is a useful
quantity [17].
In addition, for obtaining reliable epidemiological data on low doses of ionizing
radiation, it is mandatory to study very large sample sizes, as the required sample
size increases approximately as the inverse square of the dose [3]. The size of the
study cohort is important in order to distinguish the effect of the ionizing radiation
statistically from the baseline cancer incidence rate. For example, if a sample size
of 50,000 people would be needed to detect a significant cancer risk of 100 mGy,
then one would need a study group of 5 million people for an absorbed dose of
10 mGy [3].
For the atomic bomb cohort in Japan (follow-up of 86,572 survivors with differ-
ent age and different radiation exposure), the detection limit for radiation-induced
cancer lies in between 50 and 100 mSv. However, for tumors with a very low base-
line cancer risk, as thyroid cancer or childhood leukemia, the detection limit could
be as low as 20 mSv [4].
For nuclear medicine, therefore, there are only epidemiologic studies on the
diagnostic use of I-131, for which the thyroid absorbed dose is in the range of 1 Gy
[7] corresponding to an equivalent dose of 1 Sv. Today, the use of I-131 is restricted
to pre-therapeutic diagnostics, which is often followed by radioiodine therapies
with activities exceeding the diagnostic activities at least tenfold. If patients are
treated with I-131, the deterministic effects of radiation are predominant and, there-
fore, are not considered in this report.
The organ absorbed doses for other radiopharmaceuticals used in diagnostic
nuclear medicine are much smaller than 1 Gy and therefore are considered to be
below the detection limit for epidemiologic studies.
The aim of this chapter is to provide information, an overview, on epidemiologi-
cal data available for nuclear medicine procedures and on the associated risk for
children and adolescents.
4.2 Risk Definitions
4.2.1 LNT Model: Linear No-Threshold Model
Based on a comprehensive literature review, most national and international com-

mittees such as UNSCEAR, BEIR VII, and ICRP assume [6, 17, 29] that the
4 Radiation Risk from Medical Exposure in Children 53
radiation cancer risk is proportional to the radiation dose with no threshold below
which there is no cancer risk. The risk-dose response was mainly derived from the
Japanese atomic bomb survivors, because all age groups and groups of persons with
totally different radiation exposure were affected. This model fits very well for all
solid cancers but, for example, for leukemia, a linear-quadratic model is assumed
[19]. However, it is still discussed, controversially, whether there is a threshold or
not [4, 19, 27].
For extrapolating the risk from high dose (dose-rate) exposure to low doses
(dose-rates), a dose and dose-rate effectiveness factor (DDREF) of 2 was introduced
in the ICRP 60 report [16]. The linear risk estimates derived from the Japanese
atomic bomb survivors are reduced by this factor, based on the assumption of lower
biological effectiveness of radiation exposure at low doses and low dose rates com-
pared to exposures at high doses and high dose rates [17]. ICRP 103 and the
UNSCEAR report 2006 [29] still use the factor 2, whereas BEIR VII [6] recom-
mends the use of a factor 1.5. For comparing different risk assumptions, it is impor-
tant to know which factor was used.
Another problem occurs, when transforming the risk of a particular exposed
population to another, with different genetic and lifestyle characteristics. There are
no simple solutions for this problem [6, 29]. There are approaches based on relative
risk (risks resulting from radiation exposure are proportional to baseline risks) and
absolute risk transport (in which it is assumed that radiation risks do not depend on
baseline risk). The BEIR VII committee recommends a weighted estimate of both
risk transport modalities. A weight of 0.7 is used for relative risk transport and 0.3
for absolute risk transport, respectively [6].
According to the models provided by the BEIR VII Phase 2 report, those exposed
at an earlier age are in general at higher risk for cancer induction from ionizing
radiation than adults. For example, a 1-year-old child and a 10-year-old child may
have an approximately threefold and twofold higher risk, respectively, of cancer
induction than a 40-year-old adult, respectively, for the same level of exposure. In
addition, a young girl has a 30–40 % higher risk of cancer induction than a young
boy with the same level of exposure, mostly due to the risk from breast cancer [9].
4.2.2 The Use of Effective Dose in Epidemiology
The term effective dose is, according to ICRP 103 [17], a protection quantity which
provides a dose value that is related to the probability of health detriment to an adult
reference person due to stochastic effects from exposure to low doses of ionizing
radiation [16, 17, 20]. It is therefore a problematic quantity for the use in children. In
particular, the effective dose reflects the risk of the nonuniform dose distribution in
terms of a uniform or whole-body exposure. This is important for medical applica-
tions, as most medical exposures consist of nonuniform partial body irradiations.
For comparing different diagnostic procedures, or similar procedures in different
hospitals and countries, the effective dose can be very useful. Furthermore, it is a
good quantity to compare the use of different technologies for the same medical
examination. But one has to keep in mind that this only holds for patient populations
with the same age and sex distribution [17].
For this reason, the quantity effective dose should not be used for epidemiologic
studies and for sex-specific or rather individual dose and risk assessment [14, 17].
4.3 Data on Radiation Risk in Nuclear Medicine
4.3.1 Thyroid Cancer Caused by Diagnostic Exposure of I-131
In a Swedish cohort, the excess cancer risk of diagnostic I-131 applications between
1952 and 1969 was investigated in different studies [7, 12, 15]. The patient follow-
up started with the first administration of I-131 or on 1 January 1958 (since then,
data have been available from the Swedish cancer registry) for the patients who
received the examination before 1958 and was conducted until the end of 1984 [15],
1990 [12], and 1998 [7]. The studies of Holm et al. [15] and Hall et al. [12] on this
cohort excluded the first 5 years after exposure for all patients. In order to further
extend the time span and to include early cancer induction, Dickman et al. [7]
included patients as early as 2 years after exposure and extended the follow-up to
1998 and furthermore included patients with previous external radiation therapy
(XRT) to the head and neck.
The data of 36,792 mostly adult patients were included in the study; only 7 % of
the patients were younger than 20 years at the time of the first administration of
I-131. The patients were divided into two groups [7]: patients who reported previ-
ous external radiation therapy to the head and neck and patients who did not. These
groups were further divided into two subgroups:
• Patients who referred for suspicion of a thyroid tumor

• Patients who referred for other reasons
Details on the patient population included in the study and mean total adminis-
tered activities, 24-h uptake, and absorbed doses for the individual subgroups can be
found in Table 4.1.
The authors did not find any evidence of an excess cancer risk for patients who
were referred for a reason other than suspicion of a thyroid tumor and did not report
external radiation therapy [7]. However, for the patient group suspicious for thyroid
tumor, an excess risk was found.
For the group with previous external radiation therapy, both subgroups showed
an excess cancer risk, which was higher for the group with suspicious thyroid tumor.
Nevertheless, both factors – suspicion for thyroid cancer and external radiation
therapy of the head and neck – were confounding factors.
The authors did not find a dose-response relationship or variation in risk with
age, but it has to be mentioned that the cohort included only 7 % patients under the
age of 20, so this is only a vague conclusion.
It is known [1, 13] that children are much more sensitive to radiation exposure
than adults. Compared to the adult thyroid gland, the thyroid gland of children pro-
liferates more rapidly and it is therefore believed that the fast growth of the
Table 4.1 Characteristics of patients exposed to I-131 classified according to prior exposure to
external radiation therapy (XRT) to the head and neck and reason for referral [7]
No prior exposure to XRT Prior exposure to XRT
Reason for referral Reason for referral
Suspicion Suspicion
of thyroid of thyroid
tumor Other All tumor Other All
Number of 11,015 24,010 35,025 608 1159 1767
patients at risk
Observed 69 36 105 12 12 24
number of
thyroid cancers
Percentage 14 23 20 18 25 22
male
Mean age at 44 (0–74) 43 (0–74) 43 (0–74) 53 (16–74) 51 (8–74) 52 (8–74)
first exposure
(range, years)
Patients 6 7 7 0 2 1
<20 years
of age at
exposure (%)
Mean 27 (2–47) 27 (2–47) 27 (2–47) 20 (2–44) 20 (2–47) 20 (2–47)
follow-up
period
(range, years)
Mean 1.3 (1–10) 1.3 (1–9) 1.3 (1–10) – – –
number of
administered
doses (range)
Mean total 2.5 1.6 1.9 3.5 3.1 3.2
administered
activity (MBq)
Mean 24 h 39 38 39 36 36 36
thyroid
uptake (%)
Mean total 1.37 0.94 1.07 1.75 1.74 1.74
absorbed
I-131 dose to
thyroid (Gy)
radiation-injured cells is the reason for the apparent effects in children. Furthermore,
children have more years of cancer risk, because of their longer life expectancy.
A German multicenter retrospective cohort study investigating diagnostic admin-
istration of I-131 in children, with a median thyroid dose of 1 Gy, has not found any
significantly increased risk of thyroid cancer in children [11]. A detailed character-
ization of the absorbed doses with age and initial diagnoses can be found in
Table 4.2. However, in this study, the number of patients studied (789 exposed sub-
jects and 1118 nonexposed subjects) and the follow-up time were limited and
Table 4.2 Median thyroid absorbed dose for different initial diagnoses and age [10]
Median thyroid dose, Gy
Initial diagnosis n = 789 (interquartile range)
Missing values 10 1.6 (0.8–1.9)
Uncertain diagnosis 13 1.5 (1.0–2.2)
Hyperthyroidism 34 1.5 (0.9–2.6)
Hypothyroidism 61 0.3 (0.2–0.7)
Goiter 385 1.1 (0.7–1.6)
Nodular goiter 77 1.0 (0.7–1.7)
Iodine metabolism disorder 10 1.8 (1.0–3.5)
No evidence of disease 199 0.8 (0.5–1.4)
Age at first administration
0–5 years 62 0.6 (0.2–1.7)
6–10 years 85 0.8 (0.5–1.4)
11–15 years 366 1.2 (0.6–1.7)
16–17 years 276 1.0 (0.6–1.4)
All 789 1.0 (0.5–1.6)
furthermore, only a very small number of children under the age of 5 were part of
the study. For this age group, the highest thyroid cancer rate was found in the most
heavily contaminated areas after the Chernobyl accident [11].
According to these studies, there is no evidence that diagnostic exposure of I-131
causes excessive thyroid cancer cases [7, 11, 12, 15, 31].
4.3.2 Thyroid Cancer Caused by Radiation Exposure

of the Japanese Atomic Bomb and the Chernobyl Accident
Cardis et al. [5] emphasized in their article about “Risk of thyroid cancer after expo-
sure to I-131 in childhood” that the iodine deficiency and the iodine supplementa-
tion appear to be important and independent modifiers of the thyroid cancer risk
after exposure of I-131 in childhood [5]. The authors carried out a case-control
study of thyroid cancer in children younger than 15 years in 1986 and who lived in
Belarus and the Russian Federation, taking account of environmental and host fac-
tors. They found that the relative risk of thyroid cancer in exposed children in iodine
deficiency areas is three times higher than elsewhere and that an iodine supplemen-
tal diet (taken after exposure and even months after) reduced the relative risk by a
factor of three.
Richardson [25] analyzed the cancer incidences among the atomic bomb survi-
vors of Hiroshima and Nagasaki who were 20 years and older at the time of the
bombing. He used Poisson regression methods for data analyzing and deriving asso-
ciations between thyroid absorbed dose and thyroid cancer incidence by sex, age at
exposure, and time-since-exposure [25].
In most reviews [2, 28], people conclude that there is only little evidence of
radiation-induced thyroid cancer in adult atomic bomb survivors. Richardson
concludes in his article that there is evidence of an increased thyroid cancer rate
among female A-bomb survivors as compared to male survivors. Nevertheless,
these studies of atomic bomb survivors do not provide information on internal
intake of radioactive iodine [2].
4.3.3 Radiation Risk in Children
According to a recent review by Fahey et al [8] a recent reevaluation of data from

the Life Span Study of the survivors of the bombings of Hiroshima and Nagasaki
indicated an increased risk of cancers of the stomach, lung, liver, colon, breast,
gallbladder, esophagus, bladder, and ovary. No increased risk was found for cancers
of the rectum, pancreas, uterus, prostate gland, and kidney. A total of 86,600 sub-
jects were followed up for solid tumors from 1950 to 2003, and it was estimated that
there were 527 excess deaths in that population [8].
A review of the data from the Life Span Study indicates a clear relationship
between induction of solid cancer and absorbed dose at levels of more than 0.5 Gy
[8]. However, as has been shown before, the limitations of epidemiological
approaches make a risk estimate at the dose range associated with clinical nuclear
medicine (i.e., 0.01–0.1 Gy) difficult. Differences in biokinetics, dose rate, or the
fractionation of dose between the subjects considered in the epidemiological studies
and nuclear medicine patients can also affect the accuracy of the estimation.
In 2013, the United Nations Scientific Committee on the Effects of Atomic
Radiation (UNSCEAR) issued a report titled “Sources, Effects and Risks of Ionizing
Radiation” (Volume II, Annex B) on the effects of radiation exposure in children
[30]. The report included a review of data for 23 types of tumors in regard to the
evidence as to whether there was an association with ionizing radiation and whether
there was an effect based on the age of exposure (i.e., whether younger patients
were at higher or lower risk with the same level of exposure). According to the
review article by Fahey et al. [8], the report indicated that a quarter of the types of
tumors (including leukemia as well as thyroid, skin, breast, and brain) clearly dem-
onstrated higher radiation sensitivity in younger subjects. In 15 % of the types of
tumors (including bladder), children had the same level of radiosensitivity as adults.
For another 10 % of the types of tumors (most notably lung), the risk in younger
subjects was lower than that in adults. In the other 50 % of types of tumors, the
association was either too weak to draw a conclusion regarding the relationship
between risk and age (e.g., for esophagus) or no evidence that there was a relation-
ship between radiation and tumor induction at any age (Hodgkin’s lymphoma, pros-
tate, rectum, or uterus). For two types of tumors (leukemia and lung), associations
of risk with age were notably different between the BEIR VII Phase 2 report and the
2013 UNSCEAR report. There was little variation in risk at different ages in the
BEIR VII Phase 2 report, whereas there was a markedly higher risk for younger
patients in the 2013 UNSCEAR report. Conversely, the BEIR VII Phase 2 report
indicated a higher risk and the 2013 UNSCEAR report reported a slightly lower risk
of lung cancer in children [6, 9, 30].
Conclusions
• For comparing different diagnostic procedures or similar procedures in differ-
ent hospitals and countries, the effective dose can be very useful. Furthermore,
this quantity is suited for a comparison of the use of different technologies for
the same medical examination. One has to keep in mind, however, that this
only holds for patient populations with the same age and sex distribution. For
this reason, the quantity effective dose should not be used for epidemiologic
studies and for sex-specific or individual risk assessment and is, therefore, a
problematic quantity for the use in radiation risk estimates in children.
• As very large sample sizes are needed to statistically distinguish radiation-
induced cancers from the baseline cancer incidence rate at very low absorbed
doses, there exist only epidemiologic studies on the diagnostic use of I-131,
for which the thyroid absorbed dose is in the range of 1 Gy. Especially for
children and adolescents, only few data on I-131 with limited patient numbers
can be found. Therefore, it is not possible to make a reliable risk assumption
for children and adolescents.
According to these epidemiologic studies, there is no evidence that diagnostic
exposure of I-131 causes excessive thyroid cancer cases.
• For other radiopharmaceuticals used in diagnostic nuclear medicine, the
absorbed doses to the organs are too small and are therefore below the detec-
tion limit for epidemiologic studies. In this case, theoretical assumptions have
to be taken into account. The data for low doses are primarily based on the
long-term follow-up of the atomic bomb cohort and are linear extrapolations
from high-dose exposure (linear no-threshold model).
• As seen from the epidemiological data, children may be considered in general
to be at higher risk for adverse health effects from ionizing radiation than
adults. Across many types of tumors, children may be two to three times more
sensitive than adults. However, this is not true for all types of tumors; some
may demonstrate higher radiosensitivity, some less radiosensitivity, and some
similar radiosensitivity to that of adults. More data are necessary to provide
reliable, tumor-specific risk estimates.
References
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705. doi:10.1093/jnci/dji151
2. Boice JD (2006) Thyroid disease 60 years after Hiroshima and 20 years after Chernobyl.
JAMA 295:1060–1062. doi:10.1001/jama.295.9.1060
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Nuklearmedizin. doi:10.3413/Nukmed-0341-10-08
Pediatric Nuclear Medicine in Acute
Clinical Setting 5
Reza Vali and Amer Shammas
Contents
5.1 General Consideration 62
5.2 Brain Death Scintigraphy 63
5.2.1 Radiopharmaceutical and Image Acquisition 64
5.2.2 Interpretation 64
5.3 Pulmonary Emboli 67
5.3.1 Radiopharmaceuticals and Imaging Technique 69
5.4 Hepatobiliary Scintigraphy 74
5.5 Lower GI Bleeding 80
5.6 Meckel Scan 81
99m
5.7 Tc-RBC Scan 86
5.8 Renal Scan 88
5.9 Renal Cortical Imaging for Pyelonephritis 88
5.10 Renal Transplant 91
5.11 Bone Scan in Acute Care Settings 97
R. Vali, MD, FEBNM • A. Shammas, MD, FRCPC (*)

University of Toronto, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
e-mail: reza.vali@sickkids.ca; amer.shammas@sickkids.ca

DOI 10.1007/978-3-319-21371-2_5
62 R. Vali and A. Shammas
5.12 Fever of Unknown Origin 104

References 106
Abbreviations
18
F-FDG F18-2-deoxy-2-[fluorine-18]fluoro-d-glucose
67 67
Ga-citrate Gallium-citrate
99m 99m
Tc-DMSA Tc-dimercaptosuccinic acid
99m 99m
TC-DTPA Tc-diethylene triamine pentaacetic acid
99m 99m
Tc-ECD Tc-ethylcysteinate dimer
99m 99m
Tc-GH Tc-glucoheptonate
99m 99m
Tc-HMPAO Tc-hexamethylpropyleneamine oxime
99m 99m
Tc-MAA Tc-macroaggregated albumin
99m 99m
TC-MAG3 Tc-mercaptoacetyltriglycine
99m 99m
Tc-MDP Tc-methylene diphosphonate
99m 99m
Tc-MDP Tc-methylene diphosphonate
99m 99m
Tc-RBC Tc-red blood cell
99m 99m
Tc-SC TC-sulfur colloid
ALT Alanine aminotransferase
AST Aspartate aminotransferase
ATN Acute tubular necrosis
99m
BrIDA Tc-mebrofenin
CT Computerized tomography
99m
DISIDA Tc-disofenin
EANM European Association of Nuclear Medicine
FUO Fever of unknown origin
GI Gastrointestinal
LCP Legg-Calvé-Perthes
LEAP Low energy all-purpose
MD Meckel diverticulum
18
NaF F-sodium fluoride
SPECT Single-photon emission tomography
TPN Total parenteral nutrition
US Ultrasound
WBC White blood cell
5.1 General Consideration
Nuclear medicine studies play an important role in the diagnosis of certain clinical
conditions in acute clinical scenarios either as a first-line imaging modality or in
combination with other imaging techniques. In this chapter, different applications of
nuclear medicine procedures and indication and information about the interpretation
5 Pediatric Nuclear Medicine in Acute Clinical Setting 63
of examinations are discussed. The focus of this chapter is the application of different
radionuclide imaging techniques and radiopharmaceutical doses in children.
Obtaining high-quality studies in children is both challenging and rewarding. It
is important to know that in pediatric nuclear medicine, the staffs are working not
only with a child who is anxious but also with anxious parents. Thus a good com-
munication, appropriate for the child’s stage of development, is always recom-
mended. Other parameters, such as appropriate injection techniques, imaging
environment (including the use of immobilization devices or safety restraints and
distraction techniques), and the possibility of sedation, when necessary, should also
be kept in mind. Usually, it takes about twice as long to complete a procedure on a
pediatric patient as on an adult. Thus, a flexible scheduling is always necessary.
5.2 Brain Death Scintigraphy
Brain death is a clinical diagnosis referring to the complete and irreversible loss of
neurologic function [1, 2]. The essential findings in brain death are coma and apnea [2].
Before apnea testing is conducted, the possibility of reversible brain death must be
eliminated. Factors that might potentially influence the neurologic examination and
must therefore be corrected prior to apnea testing include shock or persistent hypoten-
sion, hypothermia, severe metabolic disturbances (including glucose/electrolyte imbal-
ance), the recent administration of neuromuscular blocking agents, and drug
intoxications including but not limited to barbiturates, opioids, sedative and anesthetic
agents, antiepileptic drugs, and alcohols [2]. The diagnosis of brain death requires two
examinations, including apnea testing. The clinical diagnosis of brain death is very dif-
ficult in children and infants [3]. Ancillary tests such as an electroencephalogram,
radionuclide cerebral blood flow, and cerebral angiography can complement, but are
not substitutes for, the neurologic examination. These tests are not mandatory in North
America, but they are a part of the diagnostic criteria in certain European, Asian,
Central, and South American countries [3–6]. The ancillary tests can be useful for the
following reasons: components of the examination or apnea testing cannot be con-
ducted (due to underlying conditions such as severe facial injury and pulmonary dis-
ease), the result of the neurologic examination is not confirmatory, a medication effect
may be present, or to shorten the duration of the observation period [2, 7].
CT angiography, CT perfusion, MR angiography, and transcranial Doppler have
been used as ancillary tests to confirm brain death. However, there is insufficient
evidence to determine whether these tests can accurately confirm the diagnosis of
brain death [7–9]. The most commonly used ancillary tests are EEG, four-vessel
cerebral angiography, and radionuclide scanning. Cerebral angiography is not a
simple procedure and entails that the patient be transferred from the intensive care
unit to the imaging suite, which is not feasible when the patient is unstable. A
nuclear medicine brain death study is a simple, accurate, and minimally invasive
test that evaluates brain perfusion and is usually helpful in the diagnosis of brain
death. The patient can be transferred to the nuclear medicine department, or a por-
table gamma camera can be used (if available) at the patient’s bedside.
5.2.1 Radiopharmaceutical and Image Acquisition
There are two methods by which radionuclide studies can evaluate brain function.
The conventional method is based on the evaluation of perfusion after the injection
of a nonspecific flow radiotracer such as 99mTc-pertechnetate or 99mTc-DTPA and
planar acquisition in anterior and lateral views [10]. The second method is to use
brain-specific radiotracers 99mTc-hexamethylpropyleneamine oxime (99mTc-HMPAO)
and 99mTc-ethylcysteinate dimer (99mTc-ECD) to determine flow and delayed images
after approximately 20 min [11]. Using brain-specific agents are increasingly more
popular now, since the interpretation of results is less dependent on the quality of the
bolus injection, and the delayed images are usually sufficient for a definitive diagno-
sis [12]. In addition, these studies do not need to be repeated if there is a technical
problem with the flow images [13]. This is useful, given the challenge of evaluating
blood flow to the brain stem based only on flow images [14]. However, if the quality
of delayed images is suboptimal, due to improper preparation or instability of the
radiotracer, then brain-specific images of blood flow are useful [12, 13]. The conven-
tional method of evaluating brain function by way of radionuclide studies entails an
intravenous bolus injection of 99mTc-DTPA, followed by the acquisition of dynamic
images in anterior view with 1–3 s/frame for at least 60 s [12]. The camera is placed
anterior and parallel to the patient’s head, in a way that allows both the skull vertex
and carotids to be included in the field of view. The images are acquired with a low-
energy, high-resolution collimator and a 15–20 % energy window centered around
140 KeV. It is recommended that the acquisition be initiated before the radiotracer
injection to avoid any possible loss of early blood flow to the brain [12]. Static planar
images are also acquired for the anterior view (and posterior view in some cases), as
well as one lateral view, for 500,000–1,000,000 counts per view [12]. The use of
zooming or magnification can be helpful in pediatric patients.
In the second aforementioned method, following IV injection of 11.1 MBq/kg
(0.3 mCi/kg; minimum dose of 5 mCi) of a brain-specific agent (99mTc-HMPAO or
99m
Tc-ECD), flow images are obtained with the same protocol entailed by 99mTc-
DTPA. This process is followed by delayed static images at approximately 20 min
post radiotracer injection. A SPECT study is also conducted in some centers to dif-
ferentiate between brain activity and skull uptake [15, 16]. There is no specific
process of patient preparation entailed by the brain death scintigraphy; however,
patients should be properly ventilated to avoid changes in blood flow due to
hypoventilation [12]. Some centers place a tourniquet around the head just above
the eyebrows, ears, and posterior prominence of the skull to reduce blood flow to the
skull, thus preventing confusion with brain blood flow [12]. In cases of trauma, the
tourniquet should not be used to avoid further injury to the patient.
5.2.2 Interpretation
The absence of brain activity (the so-called empty skull sign) is consistent with brain
death (Fig. 5.1), but it represents a confirmatory, rather than a diagnostic, test. In a
normal brain, after using a nonspecific brain-flow radiotracer, the activity flows up
the carotid arteries into the anterior and middle cerebral arteries. This creates a so-
called trident sign, since the two anterior cerebral arteries are seen as one line in the
middle and the middle cerebral arteries are seen on the sides [17]. Afterward, a dif-
fuse blush of activity is usually perceived, followed by visualization of the superior
sagittal sinus during the venous phase. However, superior sagittal sinus activity may
be seen in as many as 50 % of cases of brain death [18]. In a study by Coker and
Dillehay, sinus activity was detected in 14 of 55 children diagnosed with brain death
[19]. In brain death cases, the subsequent increase in intracranial pressure results in
the radiotracer not flowing up to the brain. However, flow to the external carotid
arteries usually remains intact or is even elevated, creating the so-called hot-nose
sign [20]. Because of the possibility of inadequate radiotracer injection, the study can
be repeated if the carotid arteries are not well visualized. In the case of head trauma,
the hyperemic injured area may be seen in the skull, which should not be interpreted
as brain activity [21]. Both cerebral and cerebellar activities should be assessed.
Single-photon emission tomography (SPECT) acquisition is more useful to evalu-
ate cerebellar activity or in cases of skull hyperemia or a photopenic area in the skull
Fig. 5.1 99mTC-HMPAO brain death scintigraphy in a 16-year-old female with cardiac arrest and
clinically brain death. There was no evidence of brain perfusion on perfusion images (a). No cere-
bral and cerebellar activities were also detected on delayed anterior (b) and lateral (c) images

b
resulting from hematoma or a hardware. If planar view is used exclusively, at least

one anterior and two lateral views are required, to test, respectively, for cerebral hemi-
sphere flow and cerebellar hemisphere activity. It is also advised that the images be
reviewed on the monitor with different color scales and different intensities. The final
report should include information pertaining to the radiotracer, the dose, the tech-
nique, and the extent and severity of decreased flow. According to the SNM guideline,
in the case of the absence of flow to the brain, the study should be interpreted as pro-
viding “no evidence of brain perfusion,” rather than “demonstrating brain death” [12].
Brain death scintigraphy is a reliable and accurate study. In a study by Facoo
et al., SPECT imaging confirmed the diagnosis of brain death in 95.7 %, i.e., 45 out
of 47 patients (aged 10 days to 75 years). In the other two clinically brain-dead

children (aged 10 days and 12 months, respectively), weak perfusion of the basal
ganglia, thalamus, and/or brain stem was still present, precluding the diagnosis of
brain death; both of them died a few days later [22].
Brain activity may be observed, in certain cases, especially in infants, despite the
clinical diagnosis of brain death [23–25]. Two patterns of brain death have been
described by Palmer et al. [26]. The first one, which is more common, is associated
with increased intracranial pressure. If the increased intracranial pressure is com-
pensated by a mechanism or decreased in time by reduced edema, there is a risk of
a false-negative (falsely normal) study. This may occur in infants with open fonta-
nels and flexible skulls. Posttraumatic fractures, as well as the presence of a ven-
triculoperitoneal shunt, may represent other causes of reduced intracranial pressure
[27, 28]. In the second scenario, nonfunctioning brain cells are not associated with
increased intracranial pressure. While it is not common, a diagnostic imaging
modality which evaluates only the flow to the brain may falsely be interpreted as a
negative study. Further investigation is required to confirm whether radiotracers
which show brain function such as 99mTc-HMPAO and 99mTc-ECD are more accu-
rate in these scenarios. In a study by Ashwal and Schneider, brain activity was
reported in 6 of 17 infants with clinical brain death, three of which were preterm
infants [29]. Okuyaz et al. also reported that two newborns needed a second image
to confirm the diagnosis [30]. In this study, eight patients who fulfilled the clinical
criteria for brain death were evaluated using 99mTc-HMPAO SPECT; six patients
demonstrated lack of flow activity in the cerebrum in their first SPECT study. If
there is low perfusion to the brain or clinical deterioration, it may be helpful to
repeat the study [17].
In summary, brain scintigraphy is a simple, noninvasive, reliable, and accurate
ancillary test to demonstrate whether brain perfusion is present in patients that have
been clinically diagnosed with brain death. Brain-specific radiotracers such as
99m
Tc-HMPAO and 99mTc-ECD are usually preferred. However, flow images and
delayed acquisition, as well as SPECT study (in certain cases), are essential for the
diagnosis. Cerebral blood flow may be detected in infants who are clinically brain
dead, and repeating the study may be useful, in order to demonstrate the absence of
perfusion and confirm the diagnosis of brain death.
5.3 Pulmonary Emboli
Within nuclear medicine studies performed in the acute care setting, pulmonary
emboli (PE) represent the most common indication for the evaluation of the pulmo-
nary system. PE is less common in the pediatric population than in adults. However,
with improved chances of survival in chronically ill pediatric patients, the risk of
complications such as PE has also increased [31]. Several studies show that PE is
underdiagnosed in pediatric patients; physicians usually do not ask for the neces-
sary examinations to evaluate for PE [31–34]. The clinical findings of PE in chil-
dren may be subtle and variable and may mimic other diseases [31]. Shortness of
breath, pleuritic chest pain, and hemoptysis are more common in children. In ado-
lescents, pleuritic chest pain is the most common presenting symptom, followed by
dyspnea, cough, and hemoptysis [35, 36]. Other symptoms include wheezing,
crackles, sweating, tachycardia, nausea, vomiting, syncope, murmur, cyanosis, and
pleurisy with friction rub [35, 36].
Many risk factors have been suggested as causing a predisposition in children to
thromboembolism [36]. In a study conducted in a tertiary referral hospital by Biss
et al., immobility, central venous line, and recent surgery represented the most com-
mon risk factors [33]. Cancer, vascular malformations, nephritic syndrome, long-
term total parenteral nutrition (TPN) administration, systemic lupus erythematosus,
ventriculoatrial shunts, congenital or acquired thrombotic tendencies, and acute
deep venous thrombosis are the other risk factors associated with PE in children [10,
35]. Unlike adults, clinical prediction algorithms based on clinical signs, symptoms,
and risk factors have not yet been validated in children [35, 36].
Arterial blood oxygen, erythrocyte sedimentation rate, and the electrocardio-
gram have yielded variable results for patients with PE. Chest x-ray is often nor-
mal in pediatric patients with PE. Atelectasis, pleural effusion, elevated
hemidiaphragm, infiltrates, and consolidation are nonspecific findings that may be
seen on the chest x-ray [35]. Oligemia distal to PE (Westermark sign) and a shal-
low, wedged-shaped opacity with its base against the pleura (Hampton hump) are
rarely seen [10, 35]. Conventional pulmonary angiography, long considered the
gold standard for the evaluation of PE, is infrequently used because of the avail-
ability of noninvasive imaging modalities with high sensitivity and specificity
[37]. There are limited studies available to confirm the value of magnetic reso-
nance (MR) angiography for the evaluation of PE. However, MR angiography
may play a significant role in future.
Ventilation/perfusion scan (V/Q scan) and pulmonary computerized tomography
angiography (CTA) are noninvasive studies which, depending on availability and
local protocols, are usually used in order to test for PE in adults. With CTA’s recent
increase in availability, and the high sensitivity and specificity of the study (which
is usually greater than 95 %), pulmonary CTA is now the most common procedure
for the diagnosis of PE [38]. Pulmonary emboli present as filling defects in the pul-
monary arteries on CTA. CTA can be obtained quickly in critically ill patients.
CTA presents some disadvantages, mainly a high radiation exposure dose and
the use of iodinated contrast. The effective radiation dose from V/Q scan is
1.2–2 mSv [39]. Depending on the technique, the effective radiation dose with
CTA is between 5.4 and 19.9 mSv [39–41]. If CTA is not available, a V/Q scan
may be considered, especially in order to reduce the radiation dose or if the patient
has an allergy to iodinated contrast material or renal insufficiency [36, 42]. In a
study by Stein et al., the use of an imaging algorithm with chest radiography, V/Q
scan, and CTA for patients with a clinical suspicion of PE was found to reduce
radiation exposure by 20 %, from 8.0 to 6.4 mSv, with no significant difference in
the false-negative results. When the chest radiograph is normal, Stein et al. sug-
gest performing a V/Q and acquiring CTA if there is an abnormality detected by
the chest x-ray [43].
5.3.1 Radiopharmaceuticals and Imaging Technique
5.3.1.1 Perfusion Agent

Currently, 99mTc-macroaggregated albumin (99mTc-MAA) is the radiopharmaceuti-
cal used for lung perfusion imaging. In order to be trapped in the precapillary arte-
rioles in the first pass, the size of a particle should be greater than the size of a
capillary, which is approximately 7–10 μm. The particle size with 99mTc-MAA
ranges from 10 to 90 μm (90 % between 10 and 90 μm; 60–80 % between 10 and
30 μm) and should not exceed 150 μm [44]. After slow injection into a peripheral
vein in a supine position, 99mTc-MAA particles are trapped in precapillary arterioles,
causing a temporary occlusion in a distribution proportional to regional arterial
blood flow in the lungs. If the size of the particles is too large, the distribution may
not exactly reflect the lung perfusion, as some of the particles may trap in the more
proximal arterioles. The particles are then cleared by enzymatic hydrolysis and are
eventually phagocytized by the reticuloendothelial system, with a biological half-
life of 6–8 h in the lungs.
In general, the number of particles ranges from 150,000 to 500,000, which theo-
retically obstructs approximately 0.1 % of the total arterioles [45]. However, in certain
clinical conditions, involving, for instance, pulmonary hypertension and right-to-left
shunt, and in the pediatric population, the number of particles should be reduced in
order to avoid any hemodynamically significant compromise in pulmonary circula-
tion. In children, the number of particles should be adjusted for age or weight, so that
the number of particles may be kept as low as reasonably possible. This is in order to
avoid obstruction of more than 0.1 % of the total lung capillaries [45].
In neonates, the number of pulmonary capillaries is about 10 % that of adults. By
the age of three, this number increases to 50 % of the adult number and reaches the
adult number between the ages of 8–12 years old. Thus, the number of injected
particles should not exceed 50,000 in a newborn (usually 10,000–30,000), 165,000
for a 1-year-old, and 200,000–300,000 for children between the ages of 5 and 10
(with an average weight of 20–35 kg) [45–47]. According to the North American
Consensus Guidelines, if 99mTc is used for the ventilation study, the recommended
injection doses are 2.59 MBq/kg (0.07 mCi/kg) and 1.11 MBq/kg (0.03 mCi/kg),
with a minimum dose of 14.8 MBq (0.4 mCi), if no concomitant 99mTc ventilation
study is performed [44, 48].
It is suggested that the patient lie down in a supine position for a few minutes
before injection. A direct injection is preferred (rather than into an intravenous
tube), and care should be taken not to withdraw blood back into the syringe, to avoid
the formation of small clots which may present as hot spots on the perfusion images.
If 99mTc-labeled radioaerosols or Technegas are used for the ventilation scan, then
the ventilation scan should be performed first. If 81mKr gas is used, the ventilation
scan can be conducted before or after the perfusion scan, or both examinations can
be acquired simultaneously [44, 45].
Image acquisition can be obtained using a high-resolution, low-energy or a low-
energy all-purpose (LEAP) collimator. Planar images are acquired in multiple pro-
jections (8 views are preferable) in a 128_128 or 256_256 matrix format, with
300,000–500,000 counts per image. Both lungs should be in the field of view. For
cameras with small crystals (<300 mm in diameter), a diverging collimator is pref-
erable [44]. A SPECT or SPECT/CT study may also be performed. The CT portion
is acquired with a low-dose CT for attenuation correction and anatomic correlation
[44, 45]. Several reports support that SPECT improves the performance of a pulmo-
nary perfusion study [49–52]. In the majority of those studies, the sensitivity and
specificity of the SPECT perfusion scan, in the diagnosis of PE, were at least 90 %
[49–52].
5.3.1.2 Ventilation Agents

99m
Tc-DTPA Aerosol
99m
Tc-DTPA aerosol is the most commonly used radiopharmaceutical. 99mTc sulfur
colloid aerosol may also be used, but 99mTc-DTPA is preferred in children because
of the fast renal clearance [45]. The advantage of aerosols is the ability to obtain
multiple views or a SPECT study, since radioaerosols do not wash out rapidly like
radioactive gases. 99mTc-DTPA aerosol can be inhaled through a mask connected to
a nebulizer containing a saline solution of the radiopharmaceutical. In older chil-
dren, the use of a mouth piece and nose clips is preferable [10]. The ideal aerosol
particle size is between 0.1 and 0.5 μm. Larger particles tend to deposit in the cen-
tral airways (central deposition) which may degrade the images and also lead to
inadequate radiotracer delivery to the alveoli. The patient is encouraged to rinse her
mouth during and after the inhalation phase and avoid swallowing, since the activity
in the saliva may cause high gastrointestinal activity in the esophagus and stomach.
This may lead to a difficulty in visualizing the left lower lung field [45]. The aerosol
particles cross the alveolar-capillary membrane and clear via the kidneys with a
half-life of approximately 60 min in adults [53]. This clearance may increase in
certain conditions, such as during exercise, and decrease with certain lung diseases
such as cystic fibrosis [54].
The calculated administered dose is approximately 30 mCi (1110 MBq) in
adults, adjusted in children according to body surface area and weight. The patient
should inhale enough aerosol to deposit 37 MBq (1 mCi) radiotracer in the lungs
(with a minimum activity of 10 MBq in children), to allow for sufficient count sta-
tistics [45]. When both perfusion and ventilation studies are performed with 99mTc
labeled agents, the second study should have at least three times more count rates.
Thus, it is usually suggested that the radioaerosol ventilation study be obtained
before the perfusion scan.
133
Xenon
133
Xenon is an inert gas with a half-life of 5.24 days and energy of 81 KeV. After
inhalation, 133xenon equilibrates across the alveolocapillary membrane and distrib-
utes throughout the body. The clearance of 133xenon from the body is very rapid,
with a biological half-life of approximately 30 s [43]. The usual dose for children is
10–12 MBq/kg (0.3 mCi/kg), with a minimum dose of 100–120 MBq. Because of
its low-energy photopeak, the ventilation study with 133xenon should be obtained
before the perfusion scan with 99mTc-MAA, in order to avoid downscatter from
99m
Tc (this may degrade the 133xenon ventilation images). Since the activity is rap-
idly washed out, a posterior projection is generally used, with the study being
acquired in three phases: an initial single breath-hold phase, followed by the equi-
librium and washout phase [45].
To begin the study, a closed system must be set up, with a mouthpiece connected
to the spirometer system. The patient is then asked to take a deep breath and hold it
for 5–10 s or until an image of about 100,000 counts is obtained. This is difficult for
some patients to tolerate, especially pediatric patients, or when the patient is criti-
cally ill or tachypneic. In the second equilibrium phase, after the initial breath, the
patient is asked to breathe a mixture of air and 133xenon at the tidal volume rate.
Usually two images are acquired, lasting 90 s each. In the third phase, the patient
breathes the room air and exhales into a trapping system. During the third phase,
three or four 45 s images are usually acquired. Since some of the 133xenon may
escape during exhalation and enter the room air, it is necessary, for radiation safety
procedure, to maintain a negative pressure in the room with an exhaust vent. This is
usually placed near the floor and serves to remove the heavy atoms of 133xenon
leakage.
99m
Tc-Technegas
Technegas is the other form of aerosol. It is generated by evaporating pertechnetate
at a very high temperature in a graphite crucible in the presence of argon gas. This
produces ultrafine particles of 99mTc-carbon, which acts like a gas. The majority of
particles are between 30 and 60 nm. Technegas is inhaled via a facemask in a well-
ventilated room. The inhalation may cause transient hypoxemia; this can be over-
come by giving oxygen via nasal cannula [45]. Because of the smaller particle size,
there is less central deposition in Technegas than in 99mTc-DTPA aerosols, espe-
cially in patients with obstructive airway diseases.
81m
Krypton
81m
Krypton gas is produced by a rubidium generator (81Rb/81mKr) with a very short
half-life of 13 s and emissions of a 190 KeV gamma ray. Since the half-life is very
short, only the wash-in images are feasible during inhalation. The short half-life is
advantageous because of radiation protection (there is no need for a special exhaust
system) and the low radiation dose to the lungs. The other advantage is that it can be
continuously administered, and the images can be obtained in multiple projections.
There is also a minimal need for patient cooperation, which is advantageous in cases
involving critically ill patients or children.
Because of the higher energy and short half-life of 81mkrypton, the images can
be taken alternatively with 99mTc-MAA perfusion acquisition in each projection,
without moving the patient in between. There is no downscatter from 81mkrypton
(190 KeV) energy to 99mTc-MAA (140KeV), because there is no significant activ-
ity from 81mkrypton at the time of perfusion imaging. However, the generator is
expensive, and since 81Rb has a half-life of 4.7 h, it can only be used for one work-
ing day [44, 45].
Fig. 5.2 15-year-old female with radiofrequency ablation in the right atrium admitted at hospital
for tachypnea. There was no segmental or nonsegmental perfusion and ventilation defect to sug-
gest PE
The activity should be homogeneous in both perfusion and ventilation scans

(Fig. 5.2). An uncomplicated pulmonary embolus usually presents as a perfusion
defect in a region with normal ventilation (the so-called “mismatched” perfusion
defect) (Fig. 5.3). However, other possibilities may mimic this pattern. On the other
hand, a matched defect may be also due to an embolus resulting from infarction or
to emboli superimposed on underlying parenchymal diseases. Therefore, in addition
to the presence or absence of perfusion and ventilation defects, other parameters
such as the number, size (small, moderate, or large), and pattern (nonsegmental
Fig. 5.3 16-year-old female with deep vein thrombosis and tachypnea. On lung ventilation/perfu-
sion scan, multiple mismatched perfusion/ventilation defects are noted in both lungs (more on the
right), suggestive of high probability of pulmonary emboli. Only the anterior and posterior views
are shown here
versus segmental) of perfusion and ventilation abnormalities are helpful for appro-
priate diagnosis.
Many diagnostic schemes have been introduced to aid in the interpretation of the
V/Q scan, including Biello, Prospective Investigation of Pulmonary Embolism
Diagnosis (PIOPED) and modified PIOPED (II) criteria. These criteria usually
define the likelihood of pulmonary emboli as low, intermediate, or high. However,
these criteria have not been validated in children and are not fully described in this
chapter. In practice, physicians do not usually follow strict criteria, but rather use
different criteria and their own experience (“Gestalt” interpretation) [10, 55].
Regardless of the diagnostic algorithms, the likelihood of PE is very low (<5 %) in
a normal perfusion scan. The probability of pulmonary emboli is also low when the
perfusion defects are small (<25 % of a segment), matched on the ventilation scan, or
associated with a larger abnormality on the chest radiography. The probability of pul-
monary emboli is high when there are two or more perfusion defects (at least one should
be moderate or large in size) that are not accompanied by a ventilation or chest x-ray
abnormality. The interpretation of a single moderate-sized segmental V/Q mismatch is
controversial and challenging. The risk of PE is variable with this finding, so it is reclas-
sified into the intermediate probability in modified PIOPED criteria similar to Biello
criteria [56]. Stein et al. demonstrated that if there is no underlying cardiopulmonary
disease, a single moderate-sized segmental V/Q mismatch has a positive predictive
value (PPV) of up to 86 % [57]. Thus, it can be put in the high probability category.
In practice, it is preferable to have less intermediate or indeterminate results.
Glaser et al. proposed a trinary interpretation, in which the normal, low, and very low
probabilities are interpreted as reflecting no evidence of PE, a high probability as
reflecting the presence of PE, and an intermediate probability as nondiagnostic [58].
In this study, the single segmental V/Q mismatch was categorized as a positive
PE. Glaser et al. also compared their new scheme with the traditional probability
algorithm and found similar outcomes with no significant difference in the rates of
false-negative results (P = 0.63). According to the trinary interpretation, 8.4 % of the
examinations were interpreted as PE positive, 3.5 % as nondiagnostic, and 88.1 % as
PE negative (the total number of examination studies was 664). In a pediatric sub-
group analysis of 20 children, the examinations were positive in 10 %, nondiagnostic
in 5 %, and negative in 85 %, with no false negatives using either scheme. They
concluded that the trinary interpretation scheme can be safely applied to children.
In a study by Gelfand et al. of children with no known lung disease or previous
extensive PE, it was found that the use of the Biello criteria with minimal modification
yielded a low rate of indeterminate results (15 %) [59]. Gelfand et al. point out that the
V/Q scan involves less radiation than CTA and can be safely used in children who are
suspected of having PE. In our institution, the percentage of indeterminate/intermedi-
ate studies is about 10 % (unpublished). With the use of a SPECT or SPECT/CT for
both ventilation and perfusion scans, the diagnostic accuracy of the V/Q scan will be
even greater, and the rate of indeterminate studies will decrease [60, 61]. However, the
value of SPECT or SPECT/CT for evaluating PE has not been validated in children.
In summary, the V/Q lung scan is a simple and safe examination method that
entails less radiation exposure than CTA and can be used to test for PE in children.
The indeterminate results in children and adolescents are low in the selected group
with no known history of lung disease. Therefore, it is still appropriate to perform a
V/Q lung scan in children in the evaluation of PE and in a hemodynamically stable
patient with no history of lung disease and normal chest radiograph.
5.4 Hepatobiliary Scintigraphy
Hepatobiliary scintigraphy is a noninvasive modality with high sensitivity and

specificity for the diagnosis of acute cholecystitis. It may also be useful for evalu-
ating bile leakage post liver and gallbladder operation. The hepatobiliary scan is
also helpful in the identification of biliary patency in infants with suspicion for
biliary atresia.
Although cholecystitis is less common in children than in adults, its incidence in
children is believed to be increasing [10]. It is more common in adolescent girls
than adolescent boys. Acute cholecystitis in adults is usually associated with the
obstruction of the cystic duct, secondary to cholelithiasis. Accumulated mucus
causes increased pressure and gallbladder distension, edema, and bile stasis, leading
to bacterial overgrowth and inflammation. Acute cholecystitis secondary to gall-
stones is infrequent in children but may be seen with hemolytic anemia [62].
Acalculous cholecystitis in children is usually associated with other disease condi-
tions such as sepsis, infections (e.g., streptococcal infections), vasculitis (e.g.,
Kawasaki’s disease), trauma, sickle cell disease, malignancy, and metabolic and
congenital diseases. It may also associate with prolonged total parenteral nutrition
(TPN) or occur following surgery [62–64]. In acute acalculous cholecystitis, partial
or complete obstruction of the cystic duct occurs secondary to the formation of bili-
ary sludge in the absence of gallstone. The associated inflammation and edema may
compromise blood flow and lead to bacterial infection [62, 65].
Children usually present with abdominal pain in the right upper quadrant or epi-
gastric region; this is sometimes accompanied by nausea, vomiting, anorexia, and
fever. On physical examination, right upper quadrant tenderness is the most com-
mon finding [10]. Other findings may include tachycardia, palpable enlarged gall-
bladder, and jaundice. The absence of physical findings does not exclude the
diagnosis of acute cholecystitis. Leukocytosis is a common laboratory finding [65].
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST), bilirubin,
and alkaline phosphatase levels may be elevated in cholecystitis. Laboratory tests
may be needed to exclude other causes of abdominal pain (e.g., amylase/lipase for
pancreatitis, urinalysis for pyelonephritis and renal calculi, and pregnancy tests if
the patient is of childbearing age).
Although the sensitivity and specificity of ultrasound (US) are usually less than
that of the hepatobiliary scan, US is considered the primary imaging modality in
patients with suspicion of acute cholecystitis. This is mainly because of its avail-
ability, the ease with which it is performed (at the patient’s bedside), the lack of
ionizing radiation, and the ability to evaluate for other causes of acute abdominal
pain [66]. Using US, a large gallbladder with a thickened wall and surrounding fluid
accumulation, stones, and local tenderness over the gallbladder (radiologic Murphy
sign) may be detected. The sensitivity and specificity of US are estimated to be in
the range of 40–97 % and 64–100 %, respectively, in adults [37, 67–69]. In children,
the sensitivity of the ultrasound in the detection of cholecystitis is probably lower,
likely because cholecystitis tends to be more chronic than acute [70].
CT scan is not conducted as an initial imaging test for the evaluation of chole-
cystitis but can be obtained for the evaluation of extrabiliary disorders and compli-
cations of acute cholecystitis. CT scan’s diagnostic findings include the presence
of gallstones, a thickened gallbladder wall, pericholecystic fluid collections, sub-
serosal edema, gallbladder distention, and sludge [71]. However, the sensitivity of
CT scan is less than that of the US. MRI has also been performed in acute
cholecystitis in pregnant women, with indeterminate US findings for eliminating

radiation exposure.
Hepatobiliary scintigraphy has the highest diagnostic accuracy among the diag-
nostic imaging modalities to evaluate for acute cholecystitis [66]. In a systemic
review by Kiewiet et al. examining the accuracy of different imaging modalities in
patients with suspected acute cholecystitis, the sensitivity and specificity of hepato-
biliary scintigraphy were 96 and 90 %, respectively [66]. The sensitivity of hepato-
biliary scintigraphy was significantly higher than that of ultrasound (81 %) and MR
imaging (85 %). However, in practice, hepatobiliary scintigraphy is usually reserved
for patients with indeterminate findings on US or a negative US but a high suspicion
of acute cholecystitis.
Hepatobiliary scintigraphy can be useful in differentiating between biliary atre-
sia and other causes of jaundice in infants. The clinical, biochemical, and some-
times histologic findings may be similar in neonatal hepatitis and biliary atresia
[72]. Early diagnosis of biliary atresia is important, since the outcome is most suc-
cessful with early surgery, while surgery is not indicated in patients with neonatal
hepatitis [72, 73]. In a study by Gerhold et al., the sensitivity and specificity of hepa-
tobiliary scintigraphy in the diagnosis of biliary atresia were 97 % and 82 %, respec-
tively [74].
Hepatobiliary scintigraphy is also useful in evaluating for a biliary leak after
trauma or surgery (both open surgery and laparoscopic surgery on the biliary system
and gallbladder). The clinical presentation varies widely, depending on the type of
injury and the amount of leakage. US is usually considered the initial test to inves-
tigate the presence of leakage after surgery. Fluid collection is US’ main finding
[75]. Biliary dilatation is often absent, since the biliary system is decompressed by
the leak. Bile leakage may be also detected on CT scan. In general, both US and CT
scan cannot detect active leakage, and usually, there is a need for follow-up US stud-
ies to confirm the diagnosis. Hepatobiliary scan is an accurate modality for the
detection of active bile leakage with high contrast and lack of interference from
adjacent structures or bowel gas [72, 76].

99m
Tc-disofenin (DISIDA) and 99mTc-mebrofenin (BrIDA) are the most common
radiotracers used for hepatobiliary scintigraphy [77]. These radiotracers are
injected intravenously and are rapidly taken up by the hepatocytes and excreted
into the biliary system. The administered activity for infants and children is
1.85 MBq/kg (0.05 mCi/kg), with a minimum administered activity of 18.5 MBq
(0.5 mCi). In infants with hyperbilirubinemia, mebrofenin is the preferred agent,
and in 24 h, delayed images are sometimes required; the minimum administered
activity is 37 MBq (1.0 mCi).
The patient should be fasting for 4 h prior to the test. However, fasting is not
required for the evaluation of biliary atresia in infants. For the evaluation of biliary
atresia, premedication with phenobarbital (5 mg/kg/day) for 3–5 days before
hepatobiliary scintigraphy increases bile secretion and the specificity of the test
[77]. Ursodeoxycholic acid (20 mg/kg every 12 h for 48–72 h) has also been also
used in the pretreatment regimen to stimulate bile secretion [77].
Following IV injection of the radiotracer, dynamic images are obtained in supine
position with a gamma camera equipped with high-resolution, parallel-hole colli-
mator viewing the entire abdomen, including the liver. The study is recorded with
serial 1.0 min frames for 60 min using a 128 × 128 matrix with zooming, based on
the patient size. Additional sequential static images are usually obtained based on
the indication and initial findings on the first 60 min images. For evaluation of acute
cholecystitis, if the gallbladder fails to be visualized in the first 60 min study, the
image acquisition should be extended for up to 4 h after the radiotracer injection or
30–60 min after morphine sulfate (0.04 mg/kg intravenously over 2–3 min) aug-
mentation [77]. Contraindications to the use of morphine include increased intracra-
nial pressure in children (absolute), respiratory depression in nonventilated patients
(absolute), morphine allergy (absolute), and acute pancreatitis (relative) [77]. When
there is no or questionable bowel excretion, 24 h images are sometimes required for
the evaluation of biliary atresia.
If the gallbladder does not empty significantly during the initial 60 min period,
the images will repeat after a standard fatty meal or cholecystokinin analog (sin-
calide; 0.02 μg/kg diluted with saline to 30 ml with a maximum dose of 1.4 μg/70 kg
infused for 30–45 min). Sincalide may also be used when the patient is fasting for
more than 24 h, to empty the gallbladder in order to avoid a false-positive study.
For the evaluation of a biliary leak, additional images in various projections and
in different timings (usually delayed images) are obtained in order to identify any
abnormal collection of the radiotracer.
If the gallbladder is not visualized by 60 min, the image acquisition will continue
for an additional 3–4 h or for 30–60 min after the morphine augmentation. During
this period, nonvisualization of the gallbladder on a hepatobiliary scintigraphy is
suggestive of acute cholecystitis (Fig. 5.4). However, in children, visualization of
the gallbladder does not completely exclude cholecystitis, as gallbladder visualiza-
tion, though infrequent, is possible in acalculous cholecystitis or in the partial
obstruction of the cystic duct [62]. If the gallbladder is not visualized in the first
60 min, but is seen on additional images after 60 min, the diagnosis of chronic cho-
lecystitis is suggested. Morphine augmentation at 60 min may be helpful to reduce
the time of images and the number of false-positive studies (gallbladder nonvisual-
ization in the absence of acute cholecystitis). However, in acute acalculous chole-
cystitis or partial obstruction of the cystic duct (which is more common in pediatric
patients), it may overcome functional obstruction of the cystic duct and result in a
false-negative examination [62].
The causes of a false-positive study (gallbladder nonvisualization in the absence
of acute cholecystitis) include inadequate or prolonged fasting (less than 2 h or
Fig. 5.4 Hepatobiliary scan in a 5-year-old girl with abdominal pain. Ultrasound showed a thick-
wall gallbladder. On hepatobiliary scan, there is good extraction and excretion of the radiotracer
by hepatocytes (a). The activity is visualized in the bowel at about 9 min with no evidence of
intrahepatic or extrahepatic biliary duct dilatation. Gallbladder is not visualized even on delayed
images [at 60 (b), 120 (c), and 240 (d) minutes]. Of note, at about 50 min, a focus of activity is
identified in the left upper abdomen likely due to the reflux of the radiotracer into the stomach. The
study is suggestive of acute cholecystitis or obstruction in the cystic duct
more than 24 h), severe hepatocellular disease, high-grade common bile duct
obstruction, severe concomitant illness, rapid biliary-to-bowel transit (insufficient
tracer activity remaining in the liver for delayed imaging), severe chronic cholecys-
titis, and previous cholecystectomy [77]. The causes of a false-negative study (gall-
bladder visualization in the presence of acute cholecystitis) include visualization of
a bowel loop simulating the gallbladder, acute acalculous cholecystitis, the presence
of the dilated-cystic-duct sign simulating the gallbladder, bile leak due to gallblad-
der perforation, and congenital anomalies simulating the gallbladder [77].
Hepatobiliary scintigraphy may exclude the diagnosis of biliary atresia by detect-
ing the biliary drainage of the radiotracer into the bowel (Fig. 5.5). If liver uptake is
normal and no bowel activity is identified within 24 h, a diagnosis of biliary atresia
c d
is suggested (Fig. 5.6) [78]. However, nonvisualization of the bowel activity within
a 24 h period following the radiotracer injection may be seen in other conditions,
including severe cases of neonatal hepatitis, Alagille syndrome, dehydration, sepsis,
TPN cholestasis, and bile plug syndrome in cystic fibrosis. In neonatal hepatitis, the
hepatocyte uptake is reduced and the hepatobiliary transit time into the bowel is
delayed [62]. If the hepatocyte uptake is relatively preserved but the transit to the
bowel is delayed (i.e., the bowel activity is ultimately visualized), the study is sug-
gestive of intrahepatic cholestasis [74].
Hepatobiliary scintigraphy is also useful when the presence of a bile leak is sus-
pected in patients with acute abdominal pain, especially after liver operation or chole-
cystectomy [79]. Multiple sequential images in multiple projections, including
Fig. 5.5 Hepatobiliary study in a 3-month-old boy with conjugated hyperbilirubinemia. There are
normal extraction and excretion of the radiotracer by hepatocytes with good drainage into the
bowel (a). Gallbladder is visualized at 60 min (b) and drained later (not shown here). The study
excludes the possibility of biliary atresia
delayed views, particularly in the right paracolic gutter, are often necessary to confirm
the presence of bile leakage [37]. Knowledge of the previous operation and correla-
tion with anatomical imaging (e.g., CT scan) are useful for accurate diagnosis. A
SPECT/CT may be useful in cases with equivocal findings on planar images [80].
5.5 Lower GI Bleeding
Lower gastrointestinal (GI) bleeding is relatively common in infants and children.

Although in the majority of cases it is benign and self-limited, in some cases, it is
severe and warrants prompt management. The approach is to stabilize the patient

b
and then to correct the underlying diseases. There are numerous underlying possi-
bilities including coagulopathies, Meckel diverticulum, intussusceptions, infectious
enterocolitis, intestinal duplication, malrotation with volvulus, polyps, GI allergy,
and inflammatory bowel disease. Accurate localization and detection of the under-
lying pathology is important for therapy management. Endoscopy and angiography
are commonly used to detect the site of bleeding and to identify the underlying
causes. However, in many occasions, bleeding is intermittent and the result of the
anatomical modalities is negative. 99mTc-labeled RBC scintigraphy is the most sen-
sitive imaging modality for detecting active bleeding, is noninvasive, and can depict
both arterial and venous sources of bleeding [81]. Meckel diverticulum is one of the
common causes of painless GI bleeding in infants and young children. Meckel
diverticulum scintigraphy is a simple, noninvasive method for the evaluation of
Meckel diverticulum containing ectopic gastric mucosa.
5.6 Meckel Scan
Meckel diverticulum (MD) is a true diverticulum and the most common congenital
anomaly of the GI tract [82]. This anomaly is a remnant of the omphalomesenteric
duct. Patients are usually asymptomatic. Ectopic gastric mucosa is present in
approximately 50–60 % of the symptomatic cases and in more than 95 % of those
patients who present with bleeding [83, 84]. The complications include pain, bleed-
ing and/or perforation (from the secretion of ectopic gastric mucosa), and intussus-
ceptions [83–85]. Although the complications may occur at any age, more than
50 % of patients with complications, mainly painless bleeding, are seen before 2
years of age [86, 83].
a
a
Fig. 5.6 Four-month-old girl with jaundice. On hepatobiliary scan, there was good extraction of
the radiotracer by hepatocytes (a). However, no activity was seen in the bowel at 60 (b) and
240 min (c) and even on delayed images at 24 h (d)
Different imaging modalities, including barium study, ultrasound, angiography,

and CT scan, have been introduced to detect MD [87]. 99mTc-pertechnetate is the
most common and accurate noninvasive method to investigate for MD containing
ectopic gastric mucosa with overall sensitivity of 85 % and specificity of 95 % in
children.
Meckel scintigraphy is performed after the intravenous injection of 99mTc-

pertechnetate. The administered activity is 1.85 MBq/kg (0.05 mCi/kg) with a mini-
mum dose of 9.25 MBq (0.25 mCi) and maximum dose of 370 MBq (10 mCi) [48].
b c
Patient preparation is important to perform an optimum examination. The patient is

recommended to be fasting for 4 h. However, in emergency situation, the study can
be done without fasting [88]. It is important to determine if the patient had another
study before the examination to avoid any possible interference with Meckel scin-
tigraphy. Previous use of perchlorate can suppress the gastric mucosa and should be
avoided [78, 89]. Residual barium from a prior study may result in a false-negative
examination. Previous study with in vivo RBC labeling may interfere with the study
since the injected 99mTc-pertechnetate will bind to the circulating RBCs which were
treated with stannous ion via intravenous administration of a cold pyrophosphate
kit. This is not a problem with in vitro RBC labeling scan [88].
Certain premedications may increase the sensitivity of the test. However, they
are not considered necessary for the study, especially in emergency situation.
Histamine H2-receptor antagonists, such as cimetidine, ranitidine, and famotidine,

inhibit the secretion of pertechnetate into the gastric mucosa without affecting the
uptake. The recommended dose for cimetidine is 10–20 mg/kg/day for neonates and
20 mg/kg/day for infants and older children, orally for 2 days before the study, or
300 mg in 100 mL of 5 % dextrose intravenously over 20 min, one hour before the
radiotracer injection [88]. The recommended dose for ranitidine is 1 mg/kg given
intravenously (maximum 50 mg) over 20 min, 1 h before the test [88]. For famoti-
dine, it is recommended to administer 0.25 mg/kg intravenously, 1 h before the
scanning [88]. Pentagastrin (with a dose of 6 μg/kg subcutaneously) can increase
the gastric uptake [88]. Glucagon relaxes the smooth muscles and decreases the
peristalsis of the GI tract and, therefore, decreases the washout of the tracer.
However, it decreases tracer uptake in the gastric mucosa and should be used in
combination with pentagastrin. The recommended dose for glucagon is 50 mg/kg
intravenously, to a maximum of 1 mg, diluted to a volume of 10 mL with sterile
water, infused slowly over two minutes immediately before radiotracer injection.
Glucagon should not be administered to diabetic patients [88].
Imaging usually starts immediately after the radiotracer injection, in supine posi-
tion, using high-resolution collimator. A radionuclide angiogram is acquired at
intervals of 1–5 s for 1 min to assess for vascular malformation and possibly to
detect the site of bleeding. This is followed by a continuous imaging (1 min/frame)
or sequential static images every 3–5 min, for 45–60 min in anterior projection.
Delayed static images are sometimes needed to evaluate equivocal findings or to
exclude other causes of focal activity in the abdomen and pelvis, such as urinary
activity. Lateral images can be helpful to differentiate an MD (usually is located
anteriorly) from the urinary activity (which is normally located posteriorly). Routine
post-void imaging is recommended to assess MD located adjacent to or behind the
bladder. Bladder lavage, nasogastric suctioning, repeating the study in equivocal
cases, and SPECT or SPECT/CT are other techniques that have been reported to
increase the sensitivity [88–90].
MD typically presents as a focus of increased activity in the abdomen or pelvis,

most frequently in the right lower quadrant (Fig. 5.7). The activity is usually visual-
ized a few minutes after radiotracer injection, increasing over time simultaneously
with the gastric uptake. The intensity may change over time due to intestinal secre-
tions, hemorrhage, or increased motility of the bowel. Lateral views (to differentiate
MD from ureter and bladder), upright position images (to identify fixed organs such
as the duodenum), and delayed images are helpful for accurate diagnosis. Meckel
scan has 90 % accuracy, 85 % sensitivity, and 95 % specificity to detect the ectopic
gastric tissue in children [85]. The sensitivity and specificity are much lower in
adults. A number of conditions and pathologies may also present with focal
increased activity and cause false-positive results (Table 5.1). Although they are
categorized as false positive for MD, some of them are the real pathology and need
Fig. 5.7 (a) Meckel scan in a 2-year-old boy with painless bleeding. A focal activity is visualized
in the right lower quadrant simultaneously with the gastric uptake. (b) Delayed static image
showed persistent focal uptake in the right lower quadrant. The diagnosis of Meckel diverticulum
with heterotopic gastric and pancreatic tissues was confirmed on pathology
Table 5.1 Possible causes of false-negative and false-positive results in a Meckel scintigraphy
False Mechanism Examples
negative Lack of sufficient gastric Absent or insufficient gastric mucosa
mucosa
Washout of the secreted Dilution of radioactivity as a result of hemorrhage
99m
Tc-pertechnetate Fast washout because of increased bowel movement
Impaired vascular supply Intussusception
Obstruction
Pressure from the adjacent dilated ureter, bladder, or
bowel
Poor technique Inadequate preparation (e.g., no fasting, lack of
pharmacologic intervention, prior administration of
potassium perchlorate, prior barium study, aluminum
hydroxide ingestion)
Imaging technique (inadequate timing of imaging,
lateral and postvoid images to evaluate any possible
activity behind hot organs)
Insufficient radioisotope
False Urinary system Ureter, dilated pelvis, extrarenal pelvis,
positive hydronephrosis, bladder diverticulum, vesicoureteral
reflux, ectopic kidney
Vascular Aneurysm of vessels, angiodysplasia, hemangioma,
arteriovenous shunt
Hyperemia Inflammation (e.g., inflammatory bowel disease,
gastritis, regional enteritis, colitis, juvenile colon
polyps, appendicitis, abscess, small bowel
obstruction, surgery, laparoscopy, or endoscopy)
Neoplasm (e.g., colon cancer, carcinoid, lymphoma,
uterine fibroid, leiomyosarcoma)
Other sites of ectopic Duplication cyst, Barrett’s esophagus, ectopic gastric
gastric mucosa mucosa in other sites of gastrointestinal tracer
including thr pancreas, colon, and duodenum
Others Contamination (usually from urine)
Physiologic activity (e.g., salivary or gastric
secretion)
treatment. These include duplication cysts or enteric duplication containing ectopic

gastric mucosa, intestinal obstruction, intussusception, inflammation, ulcers, and
vascular tumors. False-negative studies may be seen with a poor technique, low
uptake of gastric mucosa in infants, smaller MD, infarction or impaired blood sup-
ply to the MD, and residual barium from the previous study (Table 5.1).
99m
5.7 Tc-RBC Scan
Both 99mTC-sulfur colloid (99mTc-SC) and 99m Tc-red blood cell (99mTc-RBC) can be
used for the assessment of GI bleeding. 99mTc-RBC is generally accepted as the
radiopharmaceutical of choice for evaluating lower GI bleeding [62]. The
advantages of using 99mTc-RBCs is that it remains intravascular allowing a longer

imaging time over the course of several hours maximizing the chance of detecting
intermittent bleeding [72, 91]. Using 99mTc-RBCs scintigraphy, bleeding rates as
low as 0.1–0.4 mL/min may be detected; the lowest volume of bleeding to be
detected by angiography is 0.5 mL/min [10, 81, 92].
Alternatively, 99mTc-SC can also be used to assess lower GI bleeding. 99mTc-SC
has a high bleeding to background activity ratio which allows detecting rates as
low as 0.05–0.1 mL/min. However, imaging can be acquired only for 30–45 min
which limits the possibility to detect intermittent bleeding. In addition, the high
tracer accumulation in the liver and spleen may obscure adjacent bleeding activity
sites [10].
Before the examination, the clinical situation of the patient should be assessed to
make sure that the patient is stable or should be monitored by a physician or nurse.
History of abdominal surgery, any previous medication (may be the cause of GI
bleeding or may interfere with RBC labeling), and other diagnostic and therapeutic
studies should be reviewed [92].
There are three methods to label the RBCs: in vitro, modified in vivo, and in vivo.
The labeling efficiency is highest with the in vitro labeling (>95 %) [93]. The disad-
vantage of lower labeling efficiency using in vivo method is the possible secretion
of free pertechnetate within the gastrointestinal tracer and/or excretion of free
pertechnetate into the urinary system which may lead to false-positive results [62].
The recommended dose is calculated based on the European Association of Nuclear
Medicine (EANM) pediatric dosage card, which uses a baseline dose of 56 MBq
(1.51 mCi) multiplied by a weight-based multiple [92, 94]. The resulting minimum
administered activity is 80 MBq (2.16 mCi) for a 3 kg child and the maximum
administered activity is 784 MBq (21.19 mCi) for a 68 kg patient [92, 94].
After injection of the radiotracer, flow study is acquired for 60 s (1 s/frame) fol-
lowed by dynamic imaging for 60–120 min in supine position. It is recommended
not to obtain serial intermittent static images, and the recommended frame rate
should not exceed one frame per 60 s [92]. Additional delayed static images in dif-
ferent projections can be obtained as needed. In order to detect intermittent bleed-
ing, the patient can be imaged continuously for as long as it is practical to detect the
bleeding source [92]. If no bleeding is detected, delayed images up to 24 h may be
helpful to identify any intermittent bleeding.
GI bleeding is seen on 99mTc-RBC scan as activity outside the expected anatomic

blood pool structures, which increases progressively over time, with antegrade or
retrograde motion of tracer along the bowel lumen [92]. The movement of activity
is best detected on cinematic display and may occur very rapidly. Accurate identifi-
cation of the location of bleeding requires knowledge of the anatomy and reviewing
the cinematic display. Small bowel bleeding may be distinguished from a colonic
source by its rapid curvilinear movement through a series of multiple, small, cen-
trally located segments on cinematic display of the abdomen. In contrast, in the
large bowel bleeding, there is a linear elongated pattern of activity with peripheral
location within the abdomen [62, 92]. If the extravasated activity is visualized only
on delayed images (e.g., 24 h), the location cannot be accurately identified as the
bleeding may originate elsewhere in the GI tract with interim antegrade and retro-
grade movement [95–97]. Although some authors argued the value of delayed
images in detection of the site of bleeding, others suggested that it may have some
benefits in terms of patient management in order to decide for blood transfusion,
surgery, or angiography [92].
There are a number of findings that may be misinterpreted as the site of bleeding
(false positive), including but not limited to free 99mTc-pertechnetate (secondary to
swallowed salivary gland activity or from excreted gastric mucosa activity), blood
pool activity in other organs or hypervascular lesions (penile activity, variable uterine
activity, uterine leiomyoma), urinary activity (the activity in the kidneys, ureter, blad-
der diverticulum, pelvic kidney), vascular abnormalities (e.g., aortic aneurism), liver
hemangioma, splenosis, and inflammatory bowel disease [92]. Reviewing lateral
views and cinematic display, and correlation with anatomical modalities are usually
helpful to distinguish these findings with GI bleeding. The majority of these false-
positive findings present as a fixed activity with no antegrade or retrograde movement.
The study will be positive when the patient has an active bleed. If the image acquisi-
tion is done very late in the patient management, the chance of a negative radionuclide
study will be higher. Other pitfalls include misinterpretation because of infrequent
image acquisition or incorrect localization based on single delayed images [98].
5.8 Renal Scan
The common indications for renal scintigraphy in the acute care setting in pediatric
patients are acute pyelonephritis and renal transplant complications such as acute
rejection, acute tubular necrosis (ATN), urine leak, and vascular compromise (e.g.,
renal artery or renal vein thrombosis). Renal scan with cortical agents and renal trans-
plant scintigraphy with 99mTc-diethylene triamine pentaacetic acid (99mTC-DTPA) or
99m
Tc-mercaptoacetyltriglycine (99mTC-MAG3) are very useful in these scenarios.
5.9 Renal Cortical Imaging for Pyelonephritis
Urinary tract infection (UTI) is relatively common in children involving approxi-

mately 8 % of girls and 2 % of boys before the age of 7 years old [99]. It can be
categorized into the lower-tract infection which is limited to urinary bladder (cysti-
tis) and upper tract infection when renal parenchyma is involved (pyelonephritis).
The source of infection usually originates from the perineal contaminants (ascend-
ing); however, it can be hematogenous in origin especially in neonates [100].
Escherichia coli are the most common organisms accounting for approximately
85 % of acute pyelonephritis cases [101]. Approximately 60–65 % of children with
febrile UTIs have acute pyelonephritis, as defined by the presence of abnormalities
in the radionuclide renal cortical imaging [102]. Early diagnosis and prompt treat-
ment of pyelonephritis are important to prevent late sequelae, such as renal scarring,
hypertension, and renal failure [100]. The frequency of renal scarring following
acute pyelonephritis varies by region from 26.5 to 49 % [102].
Depending on the age of the child, the clinical presentation can be varied. Fever
may be the only sign for patients below 2 years of age. In newborns, clinical signs
and symptoms may include jaundice, sepsis, failure to thrive, vomiting, and fever.
Infants and young children may present with fever, smelling urine, hematuria,
abdominal or flank pain, and new-onset urinary incontinence. School-aged children
may have symptoms similar to adults, including dysuria, frequency, or urgency
[103]. The differentiation of pyelonephritis versus lower UTI based on clinical
symptoms is difficult in children [78]. Urine test is the first step for assessing the
UTI. Renal US is helpful to evaluate for possible congenital malformations, hydro-
nephrosis, and evidence of cystitis and pyelonephritis. However, the sensitivity of
US to detect acute pyelonephritis is relatively low [104, 105].
99m
Tc-dimercaptosuccinic acid (99mTc-DMSA) renal scan is an accurate and sim-
ple imaging modality for evaluating pyelonephritis. It is also a sensitive modality to
detect renal scarring, irrespective of the vesicoureteral reflux grade. In a study by
Temiz et al., 99m Tc-DMSA scan detected renal scars in 35 % of the kidneys, which
were reported to be normal on ultrasound [105]. 99mTc-DMSA scintigraphy can
identify the degree of renal damage and evaluate the recovery of function after treat-
ment on follow-up. 99mTc-DMSA scintigraphy has a high sensitivity and specificity
for the diagnosis of pyelonephritis [78]. 99mTc-DMSA renal scan is also helpful to
assess the differential renal function, ectopic kidney, horseshoe kidney, and the
functioning cortical tissue in a dysplastic or small kidney.

99m
Tc-DMSA is the radiotracer of choice for the evaluation of the renal cortex.
DMSA is a heavy metal chelating agent. 99m Tc-DMSA is produced by reducing
pertechnetate with stannous tin in the presence of DMSA. The exact mechanism of
cortical uptake of DMSA is still controversial; however, it is suggested that the
tracer is taken up by the proximal tubular cells, directly from the peritubular vessels.
Approximately 40–65 % of the injected dose is present in the cortex 2 h after the
injection [78, 106]. Specific uptake in the cortex gives a high sensitivity for the
detection of small scars. The 99m Tc-DMSA kit is relatively unstable, especially on
exposure to air, which may lead to decreased renal activity and increased liver
uptake. The recommended dose for 99mTc-DMSA is 1.85 MBq (0.05 mCi)/kg with
a minimum dose of 18.5 MBq (0.5 mCi) injected intravenously [48].
99m
Tc-glucoheptonate (99mTc-GH), first introduced as a brain-scanning agent, can
be used as an alternate renal cortical imaging to 99mTc-DMSA. Approximately 2 h
after intravenous injection of 99m Tc-GH, 10–20 % of the activity is accumulated in
the cortex with no significant change over 24 h which gives the possibility of more
delayed images especially in the case of retained activity in the dilated pelvicalyceal
system [107, 108]. Some authors suggest obtaining early image (first 1–3 min image
for evaluating differential renal function) and injection of furosemide or obtaining
delayed images (to minimize any interfering pelvicalyceal activity) [107, 109].
Imaging usually starts 2–4 h after the administration of the radiotracer [110].
Planar images are used to evaluate the shape and position of the kidneys, as well as
to calculate the differential renal function. Acquiring more delayed images may be
useful when the renal function is markedly reduced [78]. In children, however, addi-
tional pinhole images (usually for infants and younger children) and SPECT study
(usually for older children) are recommended to detect small cortical defects. In a
study by Mouratidis et al. on 41 children, more defects were found on SPECT
images than planar views (24 vs 20), but it was not statistically significant [111].
SPECT study is probably superior to planar imaging for better delineation of the
lesions; the sensitivity probably increases marginally [111]. Similar finding was
reported by Applegate et al. [112]. However, in a study by Brenner et al., no statisti-
cally significant difference was found in the average number of abnormal segments
detected by planar (2.1) versus SPECT imaging (2.2) [113].
Normally, the distribution of activity represents the configuration of renal cortex

with no uptake in the medulla and pelvicalyceal system (Fig. 5.8). The contours of
normal kidneys are generally round shaped and regular; however, variable shape of
the renal contours can be seen. Flattening of the lateral aspect of the superior half of
the left kidney due to splenic impression or indentations in the contour of the kidney
due to fetal lobulation are normal variants. In young children, the kidney may appear
as a triangular-shaped kidney, with flattened external sides. The kidney may be
rotated with a short transverse axis in the posterior view (the so-called “slender”
kidney). The transverse axis can also be sometimes shorter at one pole (upper or
lower) than on the other (pear shaped) [114]. Poles, especially the upper pole, may
appear relatively hypoactive in contrast with the hyperactive columns of Bertin, giv-
ing a false impression of a polar lesion [110]. External attenuation may also mimic
a cortical defect. Interrenicular septum may cause a linear area of decreased uptake
extending from the renal hilum to the renal parenchyma on SPECT study. This
should not be confused with scar [115]. Attention should also be paid to the pres-
ence of fetal lobulation [110]. The normal differential renal uptake is between 45
and 55 % [78].
Acute pyelonephritis usually presents as a single or multifocal area of decreased
cortical activity of 99m Tc DMSA with no volume loss (Fig. 5.9). Less frequently, the
involved kidney may be enlarged with diffuse pattern of decreased activity [78,
110]. Deformation of contour may or may not be present [114]. These cortical
abnormalities may resolve over several months or may lead to a permanent scar
formation. Decreased activity in renal scar is more defined and usually associated
with volume loss. Decreased cortical uptake without deformity of the contour is
likely to resolve over several months, whereas deformed contour often leads to renal
scarring [110]. A follow-up 99m Tc-DMSA study at least 6 months after acute pyelo-
nephritis is useful to evaluate the sequelae [110, 114].
5.10 Renal Transplant
Renal scanning is useful after renal transplantation in children to evaluate the func-
tion of the transplanted kidney and to detect complications. Renal scan is helpful to
diagnose patients with conditions requiring surgical management (e.g., vascular
Fig. 5.8 DMSA renal scan in a 4-year-old girl with repeat episodes of urinary tract infections.
Both kidneys show good uptake of the radiotracer with normal shape and outline. There is no defi-
nite focal decreased cortical activity or loss of volume to suggest scarring. Posterior planar image
(a), pinhole images from anterior, posterior, left posterior oblique, and right posterior oblique
views (b), and geometric mean differential function (c) are shown here

a b
c
d
Fig. 5.9 DMSA renal scan in a 1.6-month-old boy with fever and urinary tract infection; posterior
(a) and anterior (b) planar views as well as posterior left (c) and right (d) pinhole images are shown
here. The left kidney shows good uptake of the tracer with normal shape and outline. The right
kidney shows diffused nonuniform decreased cortical uptake, suggestive of pyelonephritis. There
is also a large more focal cortical defect in the mid pole laterally with relative loss of volume in the
lateral border of the right lower pole, suggestive of a developing scar. Marked improvement is seen
on follow-up DMSA scan. There is marked improvement 6 months after therapy. Posterior pinhole
images from the left (e) and right (f) kidneys are shown after the therapy
e f
compromise or ureteral obstruction), as well as those with renal transplant compli-

cations who can be managed conservatively or with medical therapy (e.g., ATN or
acute rejection) [37]. Depending on the differential diagnosis, different radiotracers
may be used. However, 99m Tc-MAG3 is the agent of choice in many conditions. In
some centers, a baseline renal scan is performed in the first 24–72 h post-
transplantation to ensure the effectiveness of the transplant surgery and to have a
baseline study for comparison in the future. Follow-up studies can be obtained,
depending on the patient’s condition [10, 72].

99m
Tc-MAG3 is the most commonly used radiotracer for evaluating renal transplant
function. 99mTc-MAG3 is actively secreted via tubular cell transport. 99mTc-DTPA
can also be used to evaluate the renal transplant function. However, since the extrac-
tion fraction of MAG3 is better than that of DTPA leading to higher kidney-to-
background ratio, 99mTc-MAG3 is necessary when the serum creatinine level is high
[72]. The usual administered dose of 99m Tc-MAG3 is 3.7 MBq (0.1 mCi)/kg, given
intravenously. If a flow study is required, the recommended dose is 5.55 MBq/kg
(0.15 mCi/kg), with a minimum dose of 37 MBq (1.0 mCi) and maximum dose of
148 MBq (4 mCi) [48]. The recommended administered dose for 99mTc-DTPA is
3.7 MBq (0.1 mCi) per kilogram of body weight (minimum, 37 MBq [1 mCi]).
Immediately following IV injection of the radiotracer, imaging is acquired for 60 s
(1 s/frame) followed by dynamic imaging in anterior view for 20–30 min. Delayed
and oblique images can be performed, if required.
A normal transplant kidney demonstrates normal flow, uptake, and transit time on a
renal scan. Acute tubular necrosis (ATN) is a relatively common complication of
renal transplant resulting from ischemic injury to the graft. ATN occurs more pre-
dominantly in cadaveric transplants than in transplants from living donors.
Parenchymal retention of the tracer with minimal or no activity in the renal collect-
ing system is the typical pattern of renal scan with 99mTc-MAG3 (Fig. 5.10). The
perfusion to the transplanted kidney in ATN is either relatively preserved or mildly
decreased. However, in severe cases of ATN, both perfusion and radiotracer uptake/
excretion may be decreased. Acute rejection is another common medical
Fig. 5.10 99mTc-MAG3 renal scan in a 12-year-old female, one day post deceased donor renal
transplant. The study shows normal perfusion (a) and extraction of the radiotracer by the trans-
planted kidney with parenchymal retention, suggestive of acute tubular necrosis (b)
complication that can be detected on renal scintigraphy. Acute rejection typically

manifests as decreased perfusion and poor uptake on 99mTc-MAG3 scan. Although
ATN and acute rejection may occur at any time after transplantation, ATN usually is
seen within the first week after the operation while acute rejection typically occurs
from 1 week to a few months after transplantation [37, 116].
Surgical complications such as ureteral obstruction, vascular compromise, and
urine leak can also be detected by renal scan. Renal Doppler US is usually the
first-line imaging examination for evaluating vascular compromise or postopera-
tive fluid collections such as abscesses, hematomas, and lymphoceles. However,
renal scintigraphy may play a complementary role in these scenarios. Urinary leak
usually occurs during the first few months after renal transplantation and may
present as a focal or diffuse area of increased activity in the abdomen outside the
margins of the transplanted kidney, ureter, and bladder [72]. A urinoma usually is
identified as a photopenic region adjacent to the kidney and may or may not be
filled by the radiotracer over time. If it is not filled on delayed images, the differ-
ential diagnosis will be a urinoma, as well as a perinephric hematoma or lympho-
cele. Hepatobiliary excretion of the activity into the bowel may be seen in <5 %
of renal scintigraphy with 99mTc-MAG3, which should not be interpreted as a leak.
Ureteral obstruction usually occurs at the site of ureterovesical anastomosis
because of edema, ischemia, or technical complications and may present as accu-
mulation of the radiotracer in the pelvicalyceal system with delayed drainage.
Renal artery stenosis or thrombosis is a rare postoperative complication and may
present as a photopenic region in the location of the renal transplant, indicative of
no or reduced perfusion to the kidney. The same pattern may be seen in renal vein
thrombosis since there are no draining collateral vessels in the transplant kidney
to drain the activity [37].
5.11 Bone Scan in Acute Care Settings
There are a number of clinical conditions in acute care settings that bone scan can
be helpful for the diagnosis. Acute osteomyelitis, traumatic lesion, avascular necro-
sis, child abuse, and fever of unknown origin are some examples.

99m
Tc-methylene diphosphonate (99mTc-MDP) is the most commonly used radio-
pharmaceutical for bone scintigraphy. This tracer concentrates at the sites of osteoid
mineralization with 99mTc-labeled bone tracers exchanging with ions in the actively
forming hydroxyapatite complex. The recommended dose for children is 9.3 MBq/
kg (0.25 mCi/kg) with a minimum dose of 37 MBq (1.0 mCi) [48]. There are many
other radiopharmaceuticals which are also useful in the evaluation of musculoskel-
etal disease such as 67gallium-citrate (67Ga), labeled leukocytes using 111In or 99mTc
for musculoskeletal infection, 99mTc-sulfur colloid for bone marrow scan, and
18
F-sodium fluoride (NaF) for bone scan.
18
F-NaF PET has been widely used in adults for evaluating both malignant and
benign bone diseases, especially when there was a shortage of 99mTc-pertechnetate
[117–119]. 18F-NaF PET has been also used for evaluating pediatric patients in
acute clinical care settings, including children with suspected abuse [120, 121].
The biodistribution of 18F-NaF is similar to that of 99mTc-MDP, but the extraction of
the tracer is more rapid by bone since there is less protein binding in the blood
[122, 123]. The extraction of 18F-NaF is also greater than that of 99mTc-MDP [119].
This allows for earlier image acquisition, usually 30–45 min after the radiotracer
injection, so the study can be completed in 1 h. The other advantage of 18F-NaF to
99m
Tc-MDP is the higher resolution of PET imaging compared with the planar and
SPECT bone scan which is especially useful for smaller complex bones [124, 125].
The disadvantage of 18F-NaF PET/CT is the higher radiation dose compared with
the conventional bone scan [119]. The recommended dose for 18F-NaF is 2.22 MBq/
kg (0.06 mCi/kg) with a minimum administered activity of 18.5 MBq (0.5 mCi)
[48]. The effective radiation dose is 0.086 mSv/Mbq for 18F-NaF PET and
0.025 mSv/Mbq for 99mTc-MDP in a 5-year-old child [119]. In adult, the radiation
dose will be approximately 70 % higher using 18 F-NaF PET than that of 99mTc-
MDP [119].
Bone scan is usually obtained 2–4 h after the injection of the radiotracer, in mul-
tiple spot views or as a whole body in anterior and posterior images. This is called the
skeletal phase or delayed images. However, scintigraphy may include blood flow (for
1 min) and blood pool (2–10 min) views, which is called a three-phase bone scan
[72]. Three-phase bone scan is useful when the information about hyperemia to the
lesion (e.g., osteomyelitis) is of interest. In pediatric population, in particular, for
evaluating small bones such as the femoral capital epiphysis, magnification technique
with pinhole collimation improves the resolution. A SPECT acquisition can improve
the sensitivity and specificity of planar images and provide better anatomic localiza-
tion [124, 125]. A SPECT or SPECT/CT imaging may particularly be useful in low
back pain, traumatic lesion of feet, and Legg-Calvé-Perthes disease [126, 125].
Knowledge of the normal distribution of bone seeking agents in children is impor-

tant to avoid misinterpretation [125]. The physeal uptake and apophyseal uptake in
children are relatively high because of rich blood supply and active enchondral ossi-
fication. Non-ossified cartilaginous structures (e.g., femoral capital epiphysis,
patella, and navicular bone) usually do not show any significant uptake; thus, they
should not be mistaken for avascular necrosis. Ischiopubic synchondrosis may
appear as a discontinuity of the inferior pubic ramus before ossification and may
present as a symmetric or asymmetric increased uptake during ossification.
Acute osteomyelitis is common in children and may occur at any age, most often
affecting children younger than the age of 5 years. The femur, tibia, and humerus
are the most commonly affected bones [72]. Because of the presence of transphy-
seal vessels extending between the metaphysis and the epiphysis, children less than
18 months of age with acute osteomyelitis are also prone to septic arthritis of the
adjacent joint. Plain x-ray may be negative or only shows soft tissue swelling in the
first few days of infection. Early diagnosis of acute osteomyelitis is critical because
prompt antibiotic therapy may prevent complications, including necrosis of bone
[127]. Radiography is usually negative for 7–10 days after infection. Periosteal
reaction or radiolucencies can be seen thereafter [128].
Three-phase bone scintigraphy is highly sensitive (about 94 %) for the diagnosis
of osteomyelitis. The specificity is also high (about 95 %) in a right clinical setting
and when there is no violated bone [129]. However, in cases of a traumatic lesion or
a violated bone, the specificity is low and further investigation is required to confirm
the diagnosis. Bone scan is helpful to differentiate cellulitis versus osteomyelitis.
Typically, in both cellulitis and osteomyelitis, there are increased flow and blood
pool at the site of infection. However, on delayed images, increased activity is usu-
ally localized in the bone with osteomyelitis, while delayed views are usually nega-
tive (non-localizing) in cellulitis [130].
Bone scan may be negative in the first 24–72 h after the osteomyelitis. In certain
cases, particularly in infants, osteomyelitis may present as a photon-deficient region
(the so-called cold osteomyelitis) [131]. This is probably due to reduced radiotracer
delivery to the site of infection as a result of increased pressure secondary to the
inflammation and edema. The antibiotic therapy and diagnostic aspiration (if clini-
cally indicated) should not be delayed because of a bone scan. Although the
increased activity at the site of infection may be reduced after antibiotic therapy, it
does not happen so rapidly and probably does not affect the result of the study at the
beginning of therapy. The risk of multifocal osteomyelitis is relatively higher in
pediatric patients. Moreover, children may not be able to clearly describe the site of
infection especially in the case of a referral pain. Thus, it is suggested to evaluate the
whole body (rather than just a localized study) to detect any possible additional
bone lesions in pediatric population [72, 124].
Legg-Calvé-Perthes (LCP) disease is idiopathic ischemic necrosis of the femoral
head which is seen predominantly in children between the ages of 4–12 years (peak
age is between 5 and 7 years old). In 15 % of cases, both hips are asynchronously
involved. Patients usually present with pain in the affected hip or with a slow onset
of painless limping. Plain radiography may be normal at early stage but may also
show joint effusion, asymmetric femoral epiphyseal size, blurring of the physeal
plate, and radiolucency of the proximal metaphysis. Bone scintigraphy is more sen-
sitive than radiography for early diagnosis and is comparable to MRI [124, 132].
The scan findings depend on the stage of the disease. Visualization of a photopenic
region in the femoral head is characteristic of LCP disease [132, 133]. Pinhole
images, particularly with the hip in maximum internal rotation, should be performed
to improve resolution [133].
Gelfand et al. reported that radiological findings may never happen, if the patient
is diagnosed early on bone scintigraphy with sufficient weight-bearing restriction
[134]. On later stages, bone scan may show increased activity due to revasculariza-
tion and remodeling. Conway et al. suggested that bone scan may have a prognostic
value in LCP disease [135, 136]. Conway et al. suggested that revascularization of
bone can occur either by recanalization of existing vessels or by the development of
new vessels (neovascularization). Recanalization is a rapidly occurring process
(minutes to weeks), whereas neovascularization is a prolonged process (months to
years). Thus, with neovascularization, there is a longer time for a complete healing,
which renders the femoral head at risk for complications such as fracture, collapse,
and extrusion. According to Conway et al., recanalization process has a characteris-
tic scintigraphic pattern, beginning with the visualization of a “lateral column,”
which is associated with a good prognosis, while neovascularization has a scinti-
graphic appearance of increased activity starting from the metaphyseal region
(“base filling” and “mushrooming”), which is associated with a poorer prognosis
[135]. The prognostic value of bone scan in LCP disease was also suggested by
Comte et al. [137].
Children with sickle cell disease often present to the emergency department with
musculoskeletal pain. It is important to differentiate sickle cell crisis resulting from
bone marrow infarction and osteomyelitis. Bone scan in conjunction with a bone
marrow imaging (with 99m Tc-SC) is helpful for definitive diagnosis [72]. An abnor-
mal bone marrow scan at the site of pain with a normal or decreased uptake on bone
scan suggests the diagnosis of infarction. A normal bone marrow scan at the site of
pain with increased uptake in the blood pool and delayed images on a bone scan is
more suggestive of osteomyelitis [138].
Skeletal trauma is usually evaluated by plain radiography. However, in certain
cases, the traumatic lesion may be occult and can be missed by radiography. Bone
scintigraphy is a sensitive imaging modality to evaluate traumatic lesions in the
entire skeleton in one study. A toddler’s fracture is an example of a traumatic lesion,
which may demonstrate subtle findings on radiography. Toddler’s fracture is a spiral
or oblique fracture that most commonly involves the tibiae in toddlers or young
children less than 8 years old. Typically, the bone scan shows diffused increased
uptake in the tibial diaphysis (Fig. 5.11). In some cases, a linear or spiral pattern of
increased activity may be seen [72].
Bone scintigraphy is also more sensitive than radiography in detecting stress
fractures. Bone scan is usually abnormal at the time of presentation and can pre-
cede plain film changes by up to a few weeks [139]. Spondylolysis is a stress
fracture of the pars interarticularis of the vertebrae that occurs most commonly in
the lower lumbar spine. Spondylolysis is the result of repetitive minor trauma such
as hyperextension, sometimes associated with congenital weakness of the pars as
a result of hereditary factors. Pars defects can be diagnosed by plain radiography,
bone scintigraphy, CT, and MRI. On bone scintigraphy, typically foci of increased
uptake are visualized on delayed images, which are more prominent on SPECT
study (Fig. 5.12) [140]. Bone scan is also useful to diagnose sacral fracture (the
so-called “H shape” pattern) or other possibilities such as osteoid osteoma in low
back pain. A SPECT study is superior to planar imaging for evaluating low back
pain in children.
Bone scintigraphy is a complementary imaging modality to skeletal survey in the
diagnosis and management of the case suspicion for child abuse [141]. Bone scin-
tigraphy is helpful when radiographs are normal or detection of additional fractures
may help in confirming the diagnosis and management. Bone scintigraphy is more
sensitive than radiographs for the detection of rib fractures and non-displaced
diaphysis fractures of the extremities. However, the sensitivity of bone scan is less
than that of radiography for skull lesions or symmetrical metaphyseal fractures. Rib
fractures in child abuse are typically seen laterally, anteriorly, and posteriorly near
the costovertebral junction [142].
18
F-NaF PET has been also used for evaluating pediatric patients in acute clinical
care settings, including children with suspected abuse and in sport-related bone
injuries [120, 121, 143–145]. In a study by Drubach et al. on 22 children younger
than 2 years, more lesions were detected on PET scan. In this study, a total of 156
fractures were identified by skeletal survey, while 200 fractures were detected by
PET. The sensitivity of PET was 85 % for the detection of all fractures and 92 % for
Fig. 5.11 Bone scan in a

1.5-year-old male with a
history of fall at day care
and inability to weight bear
on the left side. Diffused
increased activity is noted
in the left tibia, suggestive
of toddler’s fracture
detecting thoracic fractures including the ribs, sternum, clavicle, and scapula.
However, the sensitivity of PET scan was relatively lower than skeletal survey for
the detection of metaphyseal lesions [120].
The usefulness of 18F-NaF PET in sport-related bone injuries has been suggested
in many studies [144, 146]. In a study by Lim et al. on 94 children and young adults
with back pain, the possible cause of pain was detected in 55 % of patients [144]. In
this study, the higher resolution of the PET imaging and the shorter time of comple-
tion of the study from the injected time have been described as the advantages. The
radiation dose was not significantly different from the conventional bone scan
(3.5 mGy vs 2.8 mGy effective doses for a 55 kg patient for 18F NaF and 99mTc
MDP, respectively) [144]. In another study by Gamie et al. on 67 adult patients with
back pain who underwent routine X-ray, CT, and/or MRI, which failed to detect a
clear cause, 18F-NaF PET/CT showed abnormal uptake in the spine in 56 patients
(84 %). In this study, one-third (36 %) of the patients showed multiple positive
uptake in both facet joints and disk areas (20/56) [146].
Fig. 5.12 Bone scan in a 14-year-old boy with low back pain (a). There is a focal increased activ-
ity in the left posterior element of L5 (pars interarticularis region), suggestive of spondylolysis
detected on SPECT images: b (coronal), c (transverse), d (sagittal) views

In summary, bone scan with 99mTc MDP is a useful modality for evaluating many
disease conditions in acute clinical setting, including acute osteomyelitis, traumatic
lesion, avascular necrosis, child abuse, and fever of unknown origin. 18F-NaF PET
has probably the same indications as the conventional bone scan with slightly more
radiation dose but with the advantages of a higher resolution of the PET system and
shorter time to complete the study.
5.12 Fever of Unknown Origin
Fever of unknown origin (FUO) in children is defined as a fever >38.3 °C of at

least 7–10 days’ duration, with no apparent diagnosis after initial outpatient or
inpatient evaluation. This is different from the term “fever without a source” which
is used when the fever lasts for 7 days or less, after a thorough clinical history and
physical examination. In general, infections, collagen vascular diseases, and
malignancies are the most common causes of FUO in adults. In pediatric popula-
tion, although all those three causes are possible, infections demonstrate as the
predominant etiology [147].
After repeated careful history, physical examination, and initial laboratory tests,
further evaluation with specific laboratory and diagnostic tests is required. Nuclear
medicine examinations are helpful to detect the underlying pathology in many
cases. A three-phase bone scintigraphy is a sensitive imaging modality to evaluate
the skeletal system for possible diagnosis of osteomyelitis. 67Ga scintigraphy, 99mTc-
or 111In-white blood cell (WBC), and 18F-FDG-PET or PET/CT have been also used
for evaluating FUO in children.
The detail of bone imaging technique has been described under the section of bone
scintigraphy. The recommended dose of 99mTc-MDP for a bone scan in children is
9.3 MBq/kg (0.25 mCi/kg) with a minimum dose of 37 MBq (1.0 mCi). Whole-
body bone scan has the advantage of evaluating the entire skeleton in one study,
particularly in younger children or those who cannot communicate or localize their
pain (autism, cerebral palsy, etc.). It is important to obtain early images (flow and
blood pool views) and pay special attention to any abnormal focus of activity on
early images, since it may be the only finding of a soft tissue tumoral lesion or a soft
tissue inflammation/infection site.
Although 67Ga scintigraphy was considered the first-line nuclear medicine
method for the investigation of FUO in adult patients, it is now replaced with
18
F-FDG, especially in pediatric patients due to several disadvantages including
its high radiation dose and a longer time needed to wait to complete the study
[148]. The recommended dose of 67Ga in children is 1.5–2.6 MBq/kg (0.04–
0.07 mCi/kg) with a minimum dose of 9–18 MBq (0.25–0.5 mCi). Bowel
activity is a common cause for both false-positive and false-negative results in

67
Ga study. Thus, a SPECT study and delayed images are essential in most
cases.
99m
Tc- or 111In-white blood cell (WBC) scan is a useful imaging technique for the
detection of infection and inflammatory bowel disease. The recommended dose for
children is 0.15–0.25 MBq/kg (0.004–0.007 mCi/kg) for 111In-white blood cell and
4.0–5.3 MBq/kg (0.10–0.15 mCi/kg) for 99mTc-white blood cell. The radiation dose
is less with 99mTc-WBC than with 111In-WBC. Images are usually acquired 1–4 h
after the injection with delayed imaging at 16–30 h. Planar images are usually
obtained using a large-field-of-view gamma camera, equipped with a medium-
energy (for 111In) or low-energy collimator (for 99mTc). The recommended dose for
18
F-FDG is 3.7–5.2 MBq/kg (0.01–0.14 mCi/kg) with a minimum administered
activity of 37 MBq (1.0 mCi). PET/CT imaging is usually obtained 60 min after the
radiotracer injection.
For the evaluation of FUO, a sensitive imaging modality is required to detect any
possible lesion. Further evaluation is then needed to confirm the diagnosis. Bone
scan has a high sensitivity to detect any site of bone infection (osteomyelitis). The
sensitivity and specificity of labeled WBC are relatively high for the detection or for
ruling out infection. Labeled WBC scan is usually negative in other causes of FUO
such as tumors. The reported sensitivity and specificity of labeled WBC for the
detection of infection as the cause of FUO were variable with a sensitivity of
55–85 % and specificity of 74–94 % for adults [149]. In children, the information is
very limited, but it is probably useful in selected cases [10].
18
F-FDG-PET or PET/CT has been evaluated in patients with FUO over the past
two decades [150]. In a study by Jasper et al. on 69 children with FUO, 18F-FDG-
PET or PET/CT scan was helpful in the diagnosis of 45 % of the cases [151]. In this
study, the final diagnosis was confirmed in 54 % of the patients, and among them,
18
F-FDG studies were helpful in 73 %. The high sensitivity and relatively low speci-
ficity of 18F-FDG PET for diseases are considered advantages due to the wide spec-
trum of etiologies in FUO [152]. The major causes of FUO (infections, inflammatory/
collagen vascular/vasculitis, and malignancy) may be potentially detected by
18
F-FDG PET/CT [150, 153].
In summary, nuclear medicine imaging techniques have an important role in
assessing the etiology of FUO in children. Three-phase bone scan, 67Ga imaging,
labeled WBCs, and 18F-FDG-PET are useful in certain cases, based on clinical
examination and initial laboratory tests. 18F-FDG-PET has the potential to replace
other imaging modalities and can be used for the evaluation of FUO in pediatric
patients. 18F-FDG-PET can detect a wider spectrum of diseases than labeled WBCs
and is probably more sensitive than 67Ga scanning with less radiation exposure and
shorter period of time to complete the study.
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rg.255045122
Nuclear Medicine in Pediatric Cardiology
6
Pietro Zucchetta
Contents
6.1 Introduction .................................................................................................................... 115
6.2 Heart............................................................................................................................... 116
6.2.1 Radiopharmaceuticals ........................................................................................ 116
6.2.2 Stress Testing ..................................................................................................... 116
6.2.3 Image Acquisition and Processing ..................................................................... 117
6.2.4 Kawasaki Disease .............................................................................................. 117
6.2.5 Anomalous Origin of the Left Coronary Artery from the Pulmonary Artery .... 118
6.2.6 Transposition of the Great Arteries .................................................................... 119
6.2.7 Metabolic Syndromes ........................................................................................ 119
6.3 Lung ............................................................................................................................... 119
6.3.1 Radiopharmaceuticals ........................................................................................ 120
6.3.2 Patient Preparation ............................................................................................. 120
6.3.3 Image Acquisition and Processing ..................................................................... 121
6.3.4 Typical Findings................................................................................................. 121
6.3.5 Clinical Indications ............................................................................................ 122
References ............................................................................................................................... 124
6.1 Introduction
Congenital heart disease is the most common congenital anomaly, occurring in 0.8
per 100 live births, with many of these patients requiring treatment by interventional
cardiology or cardiothoracic surgery during the first year of life. Imaging algorithms
in congenital heart disease continue to evolve, with more and more information
obtained by noninvasive methods. Noninvasivity is even more relevant during the
follow-up of such patients, and nuclear medicine techniques play a significant role
in many situations.
P. Zucchetta
Nuclear Medicine Department, University Hospital of Padua, Padua, Italy
e-mail: pietro.zucchetta@unipd.it

DOI 10.1007/978-3-319-21371-2_6
116 P. Zucchetta
6.2 Heart
Nuclear medicine techniques have a well-established role in adult cardiovascular

diseases, particularly for the evaluation of myocardial ischemia, risk assessment,
and viability. The use of scintigraphy in pediatric nuclear cardiology is more lim-
ited, partly because of technical (relatively long acquisition time, limited spatial
resolution with regard to small organ size) and dosimetric limitations. Nonetheless,
scintigraphic characterization of myocardial perfusion and/or metabolism remains
in many cases a precious support for clinical decisions.
High quality informative studies are obtained only by a dedicated approach,
encompassing not only patient preparation and data acquisition, but also the clinical
indication, which can differ broadly from the adult cardiology setting. Myocardial
perfusion scintigraphy is useful in children with chest pain only when ECG and/or
echocardiographic findings are present [1].
6.2.1 Radiopharmaceuticals
Technetiated tracers represent the best choice for myocardial SPET in children.
Both 99mTc-methoxyisobutilisonitrile (99mTc-MIBI) and 99mTc-tetrofosmin have
superior imaging quality compared to 201Thallium (201Tl), which has an unfavorable
dosimetric profile, resulting in a much higher absorbed dose. Hepatic clearance of
MIBI and tetrofosmin may be slow in children, particularly in infants, with adverse
effect on the evaluation of the inferior wall of the heart in small patients [2]. In this
case, it is useful to prolong the waiting time after injection to 60–90 min.
Dose scaling should be performed following local regulations, aiming at a bal-
ance between radiation protection and the need for good quality images. Many dose
reduction algorithms have been published and some of them are periodically
adjusted to the evidence of research literature and made available online [EANM
dose calculator, SNM dose, tool etc.]. Fasting (2–3 h) is required for stress imaging
and when sedation is reasonably foreseen; it is advisable to perform rest imaging in
the same condition, to improve reproducibility.
Positron emitting radiopharmaceuticals have been used in selected cases for the
study of myocardial metabolism (18 F-FDG) and/or perfusion (13NH and 82Rb) in
children [3–5], with promising results, especially with regard to the superior spatial
resolution. The introduction of PET/MR scanner could increase the use of these
radiotracers, offering a reduced radiation dose and simultaneous morpho-functional
study.
6.2.2 Stress Testing
Physical exercise (treadmill or bicycle) can be used as stressor, starting from 5 to 6

years of age, depending on single patient’s characteristics, but pharmacologic test-
ing is more reproducible in infants and younger children, requiring less compliance
6 Nuclear Medicine in Pediatric Cardiology 117
from patient and parents [6]. Adenosine (140 mcg/kg body weight per minute by an
infusion pump for 4–6 min) has the significant advantage over dypiridamole of a
shorter duration of action (less than 30 s). Stopping the venous infusion is usually
the only action required to control the possible side effects, mostly mild and self-
limiting (flushing, vague abdominal discomfort) with no need for antagonist drugs,
such as aminophylline for dypiridamole. Caffeine-containing foods (soft drinks,
tea, etc.), teophylline, and similar drugs may interfere with adenosine action and
should be avoided for 24 or better 48 h [7]. Adenosine and dypiridamole are contra-
indicated in children with history of asthma or significant wheezing or with heart
block. Radiopharmaceutical injection should be performed using a dedicated intra-
venous line at peak exercise or when the calculated drug dose has been adminis-
tered. It is possible to contemplate the injection of the radiotracer in the same line
of drug infusion via a three-way stopcock, to reduce the stress due to multiple vene-
punctures, as is the case for many infants. However, one must interrupt the adenos-
ine infusion only for a few seconds, to avoid the rapid decrease of pharmacological
action on the coronary flow.
6.2.3 Image Acquisition and Processing
Image acquisition (180° orbit from +45° to –135°, 20–30 s/frame, high-resolution
or ultra high-resolution collimators) usually starts 60–90 min after radiopharmaceu-
tical injection. Appropriate magnification is required, depending on patient’s heart
size. A double-head camera is preferable, in order to keep the acquisition time as
low as possible, reducing the possibility of patient movement. Since motionless
acquisition is essential for good quality images, sedation is usually required in neo-
nates, infants, and in most children aged less than 5–6 years. Small hearts and pro-
portionately small defect size make iterative reconstruction and the so-called
“resolution recovery” algorithms preferable to standard image processing. It is pos-
sible to acquire gated studies (G-SPET), but significant inaccuracies in volume
determination and ejection fraction calculation could result from heart’s small size
[8] in the younger age groups, even using 10–12 intervals sampling or more, to take
in account high cardiac frequency. A normal variant of the distribution pattern of
myocardial perfusion has been described in children, showing a reduced uptake in
the antero-lateral segment of the left ventricle [9]. Moreover, the anatomy of con-
genital malformed hearts can differ largely from standard, requiring particular
attention in the identification of the ventricular chambers. In such cases, the use of
hybrid imaging with low-dose CT (SPET-CT) can be useful [10].
6.2.4 Kawasaki Disease
Kawasaki disease is an acute, self-limited vasculitis, occurring more frequently in

infants and children between ages 1 and 8 years [11]. It is associated initially with
fever, rash, adenopathy, and conjunctival and oral mucosa abnormalities. Coronary
118 P. Zucchetta
arteries are frequently involved without prompt treatment and coronary aneurysms
may develop (in up to 25 % of untreated children). About two thirds regress during
the first year after the acute illness, but some patients develop long-term coronary
stenosis, even after aneurysm regression [12–14]. Moreover, perfusion defects have
been described in the absence of detectable coronary lesions [15, 16]. They could be
related to abnormal endothelial function, which has been demonstrated in some
patients without coronary aneurysms, even years after recovery from the acute ill-
ness [17]. Echocardiography is the standard method for aneurysms identification
and follow-up, but myocardial perfusion scintigraphy is useful for noninvasive
assessment of myocardial perfusion [18] and has a role in the follow-up of patients
with persistent coronary aneurysms. The usefulness of myocardial perfusion scin-
tigraphy in the evaluation of possible long-term disturbances of ventricular micro-
circulation remains to be determined [19, 20].
6.2.5 Anomalous Origin of the Left Coronary Artery

from the Pulmonary Artery
Anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA)
is a rare (0.25–0.5 %) congenital cardiac abnormality, diagnosed mainly by echo-
cardiography and/or cardiac catheterization. It has a high mortality (up to 90 %)
during the first year life, if untreated [21, 22], but surgical repair has markedly
improved survival (mortality below 5 % in some reports) [23, 24]. Nuclear medicine
techniques can be useful in the postoperative follow-up. The extension of ischemic
myocardium detected by SPET perfusion scintigraphy is related with the delay in
functional recovery, and the presence of viable myocardium on FDG imaging is an
important prognostic predictor [25].
Myocardial perfusion imaging has been considered not helpful in patients with
anomalous origin of RCA from LCA, because the right ventricular wall is too thin
to be imaged at rest in the absence of right ventricular hypertrophy [1]. However,
technical progress could lead to a change, as has been reported in a selected group
of patients (Fig. 6.1) [26].
Fig. 6.1 Male, 9 years, anomalous origin of the left coronary artery. MIBI myocardial perfusion
scintigraphy. Reversible hypoperfusion in the anterior wall of the left ventricle
6.2.6 Transposition of the Great Arteries
Myocardial perfusion imaging has been frequently employed in children [27, 28]
after surgical intervention involving mobilization and/or reimplantation of coro-
nary arteries, as in the arterial switch operation (ASO) for the transposition of the
great arteries (TGA), where the coronary arteries are reimplanted at the time of
surgery and may be prone to kinking, abnormal vasodilation, or failure to grow at
the anastomosis level after reimplantation. Severe hypoperfusion, fixed or revers-
ible, is usually associated with perioperative complications and brings a poorer
prognosis. Perfusion defects can be detected frequently during the follow-up of
patients treated with ASO, most commonly in the apical, lateral free wall of the left
ventricle [28–30]. In most cases their size is small, and they have no influence on
the ventricular performance. Their pathophysiologic significance (i.e., microcircu-
lation disturbances or reduced endothelial function) and their prognostic value
have not been yet established. Myocardial perfusion scintigraphy has been used
also in the follow-up of TGA patients treated with the Mustard-Senning procedure
(atrial switch), where the morphological right ventricle is the systemic ventricle
and therefore develops a progressive hypertrophy, which can be complicated by
regional ischemia [31], as it has been described in univentricular correction (Fontan
procedure) [32].
6.2.7 Metabolic Syndromes
Nuclear medicine techniques have been applied to Duchenne muscular dystrophy

(DMD), which is associated with myocardial degeneration and fibrosis. Myocardial
lesions are segmentally distributed and start the basal inferior and infero-lateral
walls of the left ventricle, progressing to midinferior, apical, and anterior segments,
where a severe transmural fibrosis and fatty infiltration has been observed, with
increased glucose utilization on the FDG-PET study (perfusion metabolism mis-
match) [33].
A recent study proved the utility of myocardial perfusion imaging in Williams
syndrome, a multisystem disorder characterized by a deletion of the elastin gene,
which leads to diffuse cardiovascular alterations, often involving the coronary
arteries [34].
6.3 Lung
Pulmonary blood flow disturbances are a frequent finding in congenital heart dis-
ease. They have often heavy consequences on the blood saturation and on the devel-
opment of the child, requiring prompt treatment and a prolonged follow-up.
Furthermore, lung perfusion unbalance may be a complication of surgical manipu-
lation of the pulmonary arteries during palliative and/or corrective interventions.
Lung perfusion scintigraphy represents an effective and safe technique for the
120 P. Zucchetta
noninvasive study of pulmonary blood flow distribution and is a perfect complement

to ultrasound techniques.
6.3.1 Radiopharmaceuticals
The distribution of pulmonary blood flow can be assessed by lung perfusion scin-
tigraphy using technetium-labeled macro-aggregate of albumin (99mTc-MAA) or
albumin microspheres [35, 36]. Standard adult radioactivity dose must be reduced
according to radiation protection regulation, preferably referring to a validated
dose reduction algorithm [i.e., EANM dose calculator or similar]. A similar
reduction in the number of injected particles (Table 6.1) is required, to avoid a
significant increase in pulmonary vascular resistance, even in infants with severe
pulmonary hypertension. The method has proved to be safe even in patients with
known significant right-to-left shunts, where a further prudential reduction in the
number of injected aggregates may be advisable, to limit to a minimum dissemi-
nation in the systemic circulation. The total amount of injected particles should
not be less than 10,000–20,000, to avoid a significant deterioration of image
quality [37].
No specific preparation is required for lung perfusion scintigraphy and sedation is

not routinely indicated, at least for standard acquisition. It is highly recommended
to defer the exam when a concomitant illness (i.e., bronchopulmonary infections)
can interfere with tracer distribution. Even low-grade bronchoconstriction can result
in significant redistribution of pulmonary blood flow [38], making difficult the
interpretation of scintigraphic findings. Therefore, it is advisable to wait for the
resolution of respiratory symptoms before performing lung perfusion scan. The
tracer is administered via a peripheral vein, avoiding whenever possible injection in
a venous line, which can lead to “hot spot” artifacts. The site of administration is not
relevant when normal atrial mixing is present and both lungs are perfused through a
common blood supply. When these conditions are not met, the injection site must be
adapted to the physiology of the pulmonary blood flow, taking in account the actual
functional anatomy of the single patient. This is the case of some complex malfor-
mations or after some types of surgical repair (i.e. staged Fontan procedure), when
multiple injections are required [39] (vide infra).
Table 6.1 Suggested numbers of injected particles for lung perfusion scintigraphy in children
Body weight <5 kg 6–15 kg 16–20 kg 21–35 kg >35 kg
Particles 10,000– 50,000– 100,000– 200,000– 300,000
number 50,000 100,000 200,000 300,000
Further reduction is advisable when right-to-left shunting is present
6.3.3 Image Acquisition and Processing
Static images are acquired shortly after injection, in posterior and anterior views
(200–500 kilocounts/frame, 256 × 256 matrix, acquisition zoom adapted to
patient size), using ideally a parallel hole high-resolution collimator. Oblique
views are obtained when necessary, to clarify dubious findings. Relative lung
perfusion is usually computed using geometric mean counts from region of inter-
est (ROI) on both lungs in anterior and posterior projections. However, calcula-
tions based on the single posterior projection have been shown to differ only
slightly from values based on geometric mean [40]. Therefore it is possible to
acquire only the posterior view, without losing significant clinical data, making
easier the acquisition in infants and uncooperative children. Moreover data
obtained from anterior projection can be sometimes misleading, due to the sig-
nificant influence of heart position [41]. Extra-pulmonary tracer is usually negli-
gible and background subtraction can be useful only in few selected patients,
presenting significant right-to-left shunting and extremely hypoperfused lung. In
this case background subtraction can correct for lung counts from extra-pulmo-
nary tissue, but care must be taken to adopt the same approach in the follow-up
studies. It is also possible to quantify a right-to-left shunt, comparing the lung
counts with the total extra-pulmonary activity on a whole body image [42] or
with the brain counts [43].
6.3.4 Typical Findings
The normal distribution for pulmonary blood flow usually in the 45–55 % range
for the single lung (right + left = 100 %) and the ROI-based calculation is highly
reproducible. The most frequent abnormality observed in congenital heart dis-
ease is a diffuse unilateral reduction of relative pulmonary blood flow, in most
cases related to a stenosis of the left or (less frequently) right pulmonary artery.
Nevertheless, the same pattern can occur by multiple peripheral stenoses of the
main arterial branches or by diffuse vascular involvement affecting the whole
lung; therefore, scintigraphic imaging represents only a step before the defini-
tive diagnosis. Focal hypoperfusion, which is unusual in children with congeni-
tal heart disease, is linked more often to a single peripheral stenosis. In some
cases an apical hypoperfusion is observed on the same side of Blalock-Taussig
shunt, probably as a sequel of vascular distortion during the surgical procedure
[44, 45]. This kind of abnormality can persist after removing the shunt, but it has
usually small impact on the global distribution of the blood flow to the affected
lung. A functioning Blalock-Taussig shunt can lead to a variable underestima-
tion of the blood flow to the ipsilateral lung through a dilution effect of the
systemic blood on the radiolabeled particles arriving via the pulmonary artery.
The same dilution mechanism underlies the focal hypoactivity of lung segments
perfused by persistent aorto-pulmonary connections, as is often observed in pul-
monary atresia [46].
122 P. Zucchetta
6.3.5 Clinical Indications
Lung perfusion scintigraphy has a limited role in the early diagnostic work-up of
congenital heart disease, because diagnosis and treatment planning rely in most
cases on morphological imaging (echocardiography, MRI, cardiac catheteriza-
tion, etc.). The noninvasive evaluation of pulmonary blood flow distribution
becomes critical after surgical palliation or correction, since an unbalance in
lung perfusion may arise, without any clinical sign, even after successful uncom-
plicated one-stage correction of mild anomalies [47]. Echography can explore
only the most proximal tract of pulmonary arteries; MRI or repeated angio-
graphic studies are too invasive for simple follow-up purposes, but the combina-
tion of ultrasound and lung perfusion scintigraphy allows a prolonged follow-up
with little biological and economical cost. Therefore lung perfusion scan is indi-
cated in the follow-up of congenital heart disease whenever there is the need to
evaluate the relative distribution of pulmonary blood flow [48]. The integration
with ultrasound compensates for the inability of scintigraphy to detect a sym-
metric decrease in pulmonary blood flow, as in stenosis of the main trunk of the
pulmonary artery or in bilateral balanced stenosis. On the other side, scintigra-
phy has the capability of look into the peripheral distribution of pulmonary blood
flow without limitations related to anatomical anomalies. Typical indications for
this approach are the tetralogy of Fallot (Fig. 6.2), the isolated stenosis of the
pulmonary arteries, the monitoring after closure of a persistent ductus arteriosus
or, as an emerging indication, the follow-up of anomalous pulmonary venous
return. Even more relevant is the role of perfusion scanning in the follow-up of
staged surgical repair, as in the correction following the principle of the Fontan
circulation, where a single ventricle sustains both systemic and pulmonary
a b
Fig. 6.2 (a) Male, 6 months. Repair of tetralogy of Fallot. MAA pulmonary perfusion scintigra-
phy showing marked hypoperfusion of the left lung. (b) MAA pulmonary perfusion scintigraphy 3
months after percutaneous balloon angioplasty of the left pulmonary artery. Marked improvement
of the perfusion in the left lung
circulation and the superior and inferior vena cava flow directly in the pulmonary
arteries, through surgical anastomosis. In this situation it is mandatory to split
the dose between arm and leg injection, to evaluate correctly the contribution of
SVC and IVC to pulmonary blood flow. A single injection would give a falsely
asymmetric distribution, with a preferential flow to the right lung from the SVC
or a prevalent flow to the left lung after leg injection (Fig. 6.3) [48]. MRI imaging
can give more reliable results when a complete Fontan circulation is present
[49–52]. Stenosis of the pulmonary arteries may persist after each phase of the
staged repair, or it may arise as a consequence of surgical manipulation. The
effects of reduced blood flow on vascular and/or pulmonary development can be
corrected and even reverted with prompt treatment (surgical reintervention or,
more often, angioplasty and endovascular stenting). The combination of seriate
echographic and scintigraphic studies allows to limit the use of cardiac catheter-
ization, which can be employed only when angioplasty is required, leading to a
significant reduction of radiation exposure.
a b
Fig. 6.3 (a) Female, 4 years. Fontan circulation (SVC and IVC anastomized to the pulmonary
arteries). MAA pulmonary perfusion scintigraphy (split-dose) after injection in the upper limb:
preferential distribution from SVC. (b) After injection in the lower limb, the lung perfusion is sym-
metric. (c) Subtraction image (summed injections – upper limb injection) showing the preferential
contribution from the IVC to the left lung
124 P. Zucchetta
Lung perfusion scintigraphy has been used also in the follow-up of congenital
diaphragmatic hernia and a relationship has been demonstrated between scinti-
graphic data and long-term prognosis [53, 54].
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Endocrinology: Diagnostics in Children
and Adolescents 7
Giovanna Weber and Maria Cristina Vigone
Contents
7.1 Congenital Hypothyroidism (CH) 127
7.2 Hyperthyroidism 131
7.3 Toxic Adenoma 133
7.4 Primary Hyperparathyroidism 134
7.5 McCune-Albright 135
7.6 Congenital Hyperinsulinism 135
7.7 Pheochromocytoma 136
References 138
7.1 Congenital Hypothyroidism (CH)
The overall incidence of CH is about 1 in 2200 [1]. CH may be due to defects in

thyroidal ontogeny (a group of diseases known as thyroid dysgenesis, TD) or to
permanent forms of dyshormonogenesis, due to defects in any possible step of the
hormone synthesis pathway, or finally to transient inhibition of thyroid hormone
synthesis that may be due to several causes, for example iodine overload especially
in immature glands [2, 3]. The precise characterisation of the aetiology of CH is
important for clinical management, and it permits to choose when to avoid an
unnecessary long-term therapy or to optimize supplementation in permanent cases.
Furthermore, it can be useful for genetic counselling. Those forms of CH with an in
situ gland can be aetiologically evaluated for their transitory or permanent nature at
G. Weber
Department of Pediatrics, San Raffaele Scientific Institute, Vita-Salute
San Raffaele University, Milan 20132, Italy
M.C. Vigone (*)
Department of Pediatrics, San Raffaele Scientific Institute,
Via Olgettina 60, Milan 20132, Italy
e-mail: vigone.mariacristina@hsr.it

DOI 10.1007/978-3-319-21371-2_7
128 G. Weber and M.C. Vigone
the time of diagnosis and later at the age of 2–3 years old. Those forms that show a
dysgenesis will be considered permanent at the time of the diagnosis.
Imaging techniques have become one of the most efficient tools in defining the
cause of CH at diagnosis and later at the time of the aetiological re-evaluation. As a
matter of fact, when the gland is normally located and an aetiological diagnosis of
CH had not been done at birth, a characterisation of the permanent or transient
nature of the disease is possible at the age of two or three, when the development of
the central nervous system is completed and therapy can be safely withdrawn.
The main imaging techniques that can be used for the aetiological diagnosis of
CH are ultrasound scanning (US) and thyroid scintigraphy (TS) with either 99mTcO4
or 123I. 131I was at one time used for thyroid scanning. However, today, it should not
be used for routine thyroid imaging in children due to its very high radiation dose.
TS should be considered a complementary tool to US in the classification of
CH. The analysis of the literature shows how the frequency of dysgenetic glands
identified by TS is higher than with US (mainly due to the better identification of
ectopies). In fact, US succeeds in determining the presence of a eutopic or dysplas-
tic gland, but fails to distinguish athyrotic glands from eutopic. On the other side,
US can provide additional information not available with TS alone, regarding thy-
roid volume, presence of cysts of the thyroglossal duct or within the thyroid itself
and additional information related to neck structures (thymic tissue or other neck
massed) [2, 3]. Thus, thyroid US is now accepted as the first line of imaging diag-
nostic investigation to verify the presence of thyroid tissue in the neck. If no thyroid
tissue is detectable in the normal position on US, 99mTcO4 TS should be performed
to distinguish between thyroid agenesis and ectopy [4].
99m
TcO4 is commonly used at the time of diagnosis for its general availability and
safety [5] (Figs. 7.1 and 7.2). It is trapped in thyroid gland in the same manner as
iodine, but it cannot be organified. In fact, after trapping, it is released by the gland.
Moreover, 99mTcO4 uptake is not limited to thyroid tissue but also to salivary glands
Fig. 7.1 Thyroid ectopy

7 Endocrinology: Diagnostics in Children and Adolescents 129
Fig. 7.2 Thyroid agenesis
which may pose difficulties to prove the presence of an ectopic gland. This problem
may be overcome rinsing the children’s mouth with lemon juice and water to stimu-
late salivary activity and wash out the radioiodide. Furthermore, the presence of
antibodies against TSH receptor or mutations on the NIS gene (Sodium Iodide
Symporter) can show a false dysgenesis. Imaging is performed 20–30 min after
intravenous injection of the isotope. Normally TS in children does not normally
comprise a preparation phase. However, it is important to investigate and withdraw
possible medications that may interfere with the study: thyroid hormones, iodine-
containing drugs, antithyroid drugs, X-ray contrast media and lithium. Furthermore,
the use of 99mTcO4-tin complexes for a recent scintigraphic imaging can interfere
with the study. Important is to prevent motion artefacts, when small children are
tested. To do so, fixation supports may be helpful. TS normally lasts between 5 and
15 min, and a gamma camera is used to detect the signal. As regards the interpreta-
tion of the scintigraphic study, up to present, no specific age-related data are avail-
able for thyroid uptake. The general guidelines used for adults may be useful: 5 %
for maximal basal 99mTcO4 uptake.
On the other side, 123I can be of more difficult availability and of higher costs. It
is trapped and organified by the thyroid gland [5]. The sensitivity of TS when using
123
I is higher than with 99mTcO4 due to the ratio of organ to background activity, ten
times higher with 123I. However, the short half-life of this isotope (about 13 h) and
the difficult availability explain why it is not of frequent use at the time of diagnosis.
In fact, 123I is mainly used nowadays for the differential diagnosis of inborn errors
of hormonogenesis in children with an in situ gland, at the time of etiological re-
evaluation at 2–3 years old [4]. In these cases a so-called depletion test can be per-
formed. It consists of an intravenous or oral administration of I123 which is followed
by a baseline scintigraphic measurement obtained 30 min and 2 h after the injection.
When the baseline uptake of 123I is high, a blocker of the organification process,
called perchlorate, can be administered immediately after the radioactive iodide.
Afterwards, scintigraphic measurements are obtained again 15, 30, 60 and 90 min
after the administration of perchlorate. In case of defects in the organification path-
way, iodine will be released by the gland after perchlorate. Injectable and oral forms
of perchlorate are available. When perchlorate is used, a fall of below 10 % is
considered normal, while a fall between 10 and 50 % indicates a mild partial organi-
fication defect and a fall between 50 and 90 % indicates a severe partial organifica-
tion defect. A relative fall of over 90 % indicates a complete organification defect
[6] (Fig. 7.3) (Table 7.1).
As concerns the dose administered, it is very low with both isotopes. Furthermore,
in children with athyrosis, hypoplasia, and defective thyrotropin hormone receptor
(RTSH) or sodium/iodide symporter (NIS), the isotopic uptak is very low or absent.
The only case where a significant isotopic dose can be described is when the uptake
is preserved (ectopic glands, thyroglobulin defect, iodotyrosine dehalogenase
defects and in transient forms). However, no reports have been made to describe
adverse outcomes in these patients.
Fig. 7.3 Fall of over 90 % at perchlorate test at etiological re-evaluation

Positive CH screening
US
No detectable thyroid tissue In situ gland detectable
At 2−3 years, after 1 month of

At birth therapy suspension
99mTcO TS 123I TS + Perchlorate
4
Ectopy Iodine release <10 % Normal
athyreosis Iodine release >10 % and <50 % Mild partial organ

defect
Iodine release >50 % and <90 % Severe partial organ

defect
Iodine release >90 % Total organ defect
Table 7.1 Uses of scintigraphy in CH
Finally, a possible alternative to L-thyroxine withdrawal is to perform a so-called

rhTSH test [7]. The test can be performed very early in postnatal life. After the
administration of a TSH analogue (rhTSH – Thyrogen), serum TSH, free T4, free
T3, thyroglobulin levels and anti-thyroglobulin/anti-thyroperoxidase antibody lev-
els are measured. Furthermore, an ultrasound examination and a thyroid scintigra-
phy with 123I and a discharge test can be performed. This approach permits to
distinguish between permanent and transient forms of CH with an in situ gland,
preventing the unnecessary prolongation of replacement treatment in transient
CH. However, the diffusion of the test is still limited by the high costs that explain
why it is poorly used worldwide.
7.2 Hyperthyroidism
Nuclear medicine is not considered a diagnostic tool in the management of hyper-

thyroidism, while it has a primary importance in the definitive treatment of this
disease. The optimum therapeutic strategy for hyperthyroidism still represents a
controversial topic in paediatric endocrinology. Medical therapy, radioactive iodine
(RAI) therapy and surgery (thyroidectomy) are the current treatment approaches for
Graves’ disease [8]; nevertheless only 30 % of medical treated children achieve
remission [9].
Radioactive iodine therapy is a valid treatment strategy in case of refractory
hyperthyroidism or relapse of the disease despite thioamides, low compliance with
medical therapy and adverse drug reactions [10]. Controversially, while in Europe
this treatment is not usually recommended in the prepuberal period, in the USA it is
considered a first-line therapy for children >10 years of age and a second-line strat-
egy in patients 5–10 years who failed with medical therapy [8].
RAI therapy’s main goal is to induce hypothyroidism by thyroid ablation: radioac-
tive iodine is trapped by thyrocytes with high affinity, and either gamma or beta radia-
tions, which are responsible for the therapeutic effect, are emanated. Fixed or
individually calculated doses of 131I on gland size and on RAI uptake are alternatively
used, both with optimal outcomes (Table 7.2). However, large glands (>80 g) should be
surgically treated since RAI therapy seems not to be effective [8, 10], and eventually a
steroid therapy is the gold standard in case of active ophthalmopathy [10].
Radioactive 131I can be given orally, or rarely intravenously. Patients should not
take antithyroid drugs from 3 to 5 days before the treatment to at least 7 days after.
Moreover, iodine-containing products (e.g. cream, disinfectant, hair dye, amiodarone,
contrast agents) should be avoided in the period before the RAI therapy as a low-iodine
diet should be followed. By 2–3 months, patients develop hypothyroidism, while
retreatment is indicated if hyperthyroidism persists 4–6 months after the therapy [10].
The main side effects of the treatment are summarised in Table 7.3.
Acetaminophen or nonsteroidal anti-inflammatory agents are useful in case of
mild tenderness over the thyroid, which could occur in less than 10 % of the
patients [8]. In case of uncontrolled hyperthyroidism (fT4>60pMol/L), it is recom-
mended to normalise fT4 levels before the therapy, in order to avoid a secondary
thyroid storm. There is no evidence of association between 131I and genetic damage
in the patient, as no cases of thyroid cancer and other tumours have been reported in
patients treated with >5.5 MBq of 131I per g of tissue. Therefore, low doses have to
be avoided, since there is a higher risk of developing a cancer in presence of residual
thyroid tissue especially in young children [10].
Table 7.2 Fixed and individually calculated doses of 131I

Fixed dose 15 mCI
Individually calculate dose >5.5 MBq per gram of thyroid tissue weight
7.4–11.1 MBq per gram of thyroid tissue, if larger gland
(30–80 g)
Table 7.3 Side effects Thyroid tenderness (first week)

Thyroid storm
Worsening of ophthalmopathy
Thyroid cancer/thyroid nodules
7.3 Toxic Adenoma
Toxic adenoma is a hyperfunctioning nodule that results in hyperthyroidism [5].

Amongst the causes of hyperthyroidism it represents a rare one, in particular if
compared to the most frequent one, which is Graves’ disease. Toxic adenomas are
also referred to as toxic autonomous nodules and Plummer disease and are charac-
terised by an autonomous and continuous production of thyroid hormone that does
not respond to the normal hypothalamic-pituitary control mechanisms. Moreover,
the excess of thyroid hormone suppresses the further production of hormones in the
residual normal gland. Unlike Graves’ disease, the mechanism of toxic adenoma is
not autoimmunity. In fact, it is thought that the TSH receptors on the surface of the
adenoma undergo gene mutation becoming permanently active.
Adenomas can frequently present with forms of subclinical hyperthyroidism: the
affected children show suppressed TSH values, elevated T3/T4 values without anti-
bodies against TSH receptor.
Ultrasound imaging represents the first-line screening tool to detect thyroid nod-
ules. It is fundamental in assessing the number of nodules. US imaging shows a
mass lesion with variable features. Echogenicity can be diminished or increased and
homogeneous or heterogeneous. Normally they are described as hypovascular.
As concerns the scintigraphic findings, children with toxic adenomas will typi-
cally show a solitary nodule with a significant radioiodide uptake, also called “hot
nodule”, while the rest of the gland shows a diminished uptake (Fig. 7.4). This is
due to the negative pituitary feedback on TSH secretion, leading to a decreased or
absent tracer uptake.
These lesions can be treated surgically or with radioiodine. The former is at pres-
ent the preferred one in childhood, due to the high doses of isotope necessary when
using the latter technique.
Fig. 7.4 Scintigraphy of a toxic adenoma

7.4 Primary Hyperparathyroidism
Ninety percent of hypercalcemia associated to primary hyperparathyroidism cases

are due to an adenoma in a single parathyroid. The preoperative localization with
ultrasonography and radionuclide scintigraphy allows a selective surgical excision
of the hyperfunctionating parathyroid gland [11]. In the past, when preoperative
imaging was not used, the unguided bilateral surgery failed in 5–10 % of patients,
especially in the presence of an ectopic parathyroid or a multiple gland disease.
While the advantages of radioguidance – a reduction in conversion to bilateral
exploration, operative time, length of stay and total costs – have been well defined
in adults, in paediatric patients only few studies have examined the utility of preop-
erative localization with radionuclide [12].
99m
Tc-sestamibi scanning was first introduced in cases of persistent and recur-
rent hyperparathyroidism after surgery. Currently, it is a routine diagnostic exam,
run before first-time parathyroidectomy, and its main goals are to detect either
abnormal or ectopic parathyroid gland and to differentiate between a single ade-
noma and multiple diseases [13]. The tracer is not uptaken in normal glands; in
fact 99Tc diffuses passively across cell membranes and concentrates in mitochon-
dria of oxyphil cells in hyperplastic parathyroid, cardiac cells and thyroid tissue.
The slower washout from abnormal parathyroid than from thyroid plays a central
role in the exam [11].
Patients must be off any thyroid medication and should not undergo any iodine
contrast imaging procedure for 6 weeks prior to the exam [13]. The tracer, with an
activity of 200 MBq in adults and modified according to Piepsz et al. in children,
is intravenously injected [5]. Different protocols are used (Table 7.4). In order to
avoid the cons of each technique, another preoperative tool is represented by simul-
taneous recording of 123I and 99mTc. Moreover, three-dimensional information and
a higher sensitivity can be obtained using SPECT with 99mTc, alone or combined
with CT [11].
Table 7.4 Protocols: single-phase dual-isotope subtraction versus dual-phase single-isotope

subtraction
99m
Single-phase Tc sestamibi (taken up Residual radioactivity on The patient has to be
dual-isotope by parathyroid and the subtraction image identically
subtraction thyroid), then 123I or positioned for the
99m
Tc pertechnetate two studies.
(taken up by thyroid
only)
Dual-phase Single injection of Slower washout from Low sensitivity for
99m
single-isotope Tc sestamibi and hyperfunctioning primary hyperplasia
subtraction imaging at 10–15 min parathyroid gland
and 1.5–3 h after the
injection
Table 7.5 Diagnosis

Category Main features Strategy
Definite Typical radiological features No further diagnostic investigation
diagnosis Radiological features + cafè au lait
spots/or precocious puberty/or
myxoma
Several radiological features
Probable Several radiological features, no 1. RX
diagnosis clinical features 2. CT
3. MRI
4. Scintigraphy
Doubtful Lesions discovered by MRI or bone CT/MRI to detect signs of activity and
diagnosis scintigraphy scintigraphy to search typical lesions
Few radiological features If doubt, or cancer, obtain bone biopsy
Previous neoplasia
7.5 McCune-Albright
Polyostotic fibrous dysplasia, cafè au lait skin spots and autonomous endocrine hyper-
function (precocious puberty, hyperthyroidism, growth hormone excess, Cushing syn-
drome and renal phosphate wasting) are the main features of the rare McCune-Albright
Syndrome (MAS) [14]. Essential diagnostic information is provided by bone imag-
ing, and according to the category in which each lesion is assigned, appropriate fur-
ther diagnostic strategy should be followed (Table 7.5). Plain radiographs show a
typical “ground glass” bone with lytic lesions involving usually the metaphysis and/or
the diaphysis of long bones. No bone is exempt: ribs, pelvis, spine, skull base, sphe-
noid, ethmoid and frontal mandibular bones can be involved [15].
An increased uptake of 99mTc-methylene diphosphonate (MDP) is the typical
hallmark of these lesions. Bone scintigraphy is recommended in order to map the
skeletal lesions, identify the extension of the disease, quantify the skeletal disease
burden and finally predict functional outcomes [15].
7.6 Congenital Hyperinsulinism
A key point in the diagnostic and therapeutic process of congenital hyperinsulinism

(CHI) is the histological identification of the pancreatic lesions that determine an
unregulated insulin secretion and the consequent severe hypoglycemia. Indeed, the
differentiation between focal and diffuse alterations guarantees an appropriate man-
agement of the disease. Hepatic portal venous sampling (PVS), arterial calcium
stimulation test/venous sampling test and tolbutamide response test are invasive
and, as CT or MRI, not accurate in distinguishing between a focal and a diffuse
lesion [16, 17].
Table 7.6 Interfering drugs Diazoxide 5 days

Octreotide 2 days
Glucagon 12 h
Therefore, in 2005 Riberio et al. first described the use of 18F-DOPA-PET in

CHI. [F] L-DOPA, which is synthesised from tyrosine, is picked up by pancreatic
islets, where a DOPA decarboxylase converts it to dopamine. The radioactive iso-
mer 18F-L-DOPA is decarboxylated as well as endogenous DOPA and stored either
in endocrine and exocrine pancreatic cells up to ectopic lesions, typically localised
near the head of the pancreas [16, 17].
Patients should stop taking any drug that could interfere with pancreatic cell
function before the procedure (Table 7.6).
Plasma glucose has to be monitored before and every 60 min during the exam,
and it is possible to control hypoglycemia with intravenous dextrose infusions, use-
ful in enhancing the elimination of the radioisotope from the kidneys too. After
intubating and sedating the patients with general anaesthesia, 3–6 MBq/kg (0.08–
0.16 mCi/kg) of 18 F-DOPA (one-tenth of the total adult dose) is injected intrave-
nously, and five–six consecutive 10 minute-long scans are taken [18].
A generalised and increased tracer uptake, greatest in the head (SUV 5.0) than in
the body (SUV 3,2) or the tail (SUV 3,0), is the typical evidence of a diffuse pan-
creatic lesion [17], while, in the focal subtype, 18F-L-DOPA is only taken up by the
lesion. Therefore, with a 96 % accuracy, focal and diffuse lesion can be diagnosed
and all (100 %) the focal subtypes localised [18].
Currently, 18F-DOPA-PET is recommended in children with congenital hyperin-
sulinism not responsive to medical treatment or in whom the genetic test is inconclu-
sive or positive for a focal lesion. Focal lesion can be accurately localised and then
surgically removed with a limited pancreatectomy. On the contrary, patients suffering
from unresponsive and diffuse CHI still require a total pancreatectomy [18].
7.7 Pheochromocytoma
Pheochromocytomas are tumours that originate from the paraganglionic cells any-
where in the autonomic nervous system [5]. They occur in children in 10 % of cases,
and the majority of them originate in the abdomen and predominantly in the adrenal
medulla (90 %). Some characteristics are more common in children than in adults:
bilaterality, concurrent intra- and extra-adrenal tumours, multiplicity of tumours,
recurrencies and severity of symptoms. Generally pheochromocytomas present as
sporadic events, but in 10 % of cases they can be part of an inherited disorder such
as multiple endocrine neoplasia (MEN IIa or IIb). About 10 % of pheochromocyto-
mas are malignant, and malignancy is more common when an extra-abdomen mass
is present. Malignancy can often be defined only by the presence of metastasis
rather than by histologic appearance. The majority of pheochromocytomas are hor-
monally active; they can secrete parathyroid hormone, calcitonin, gastrin, serotonin
and adrenocorticotropic hormone (ACTH) with or without catecholamines.
The clinical presentation is dependent on the mass effect and on the series of
hormones produced by the tumour.
Diagnosis normally requires the measurement of 24 h urinary catecholamines
and metanephrines and/or the dosage of circulating catecholamines in blood.
However, imaging tests are of fundamental importance to detect the primary mass
and possible metastasis. The main imaging tools available are magnetic resonance
imaging (MRI), computed tomography (CT), scintigraphy with I-123-MIBG and
F-18-FDG-PET [19].
MIBG is a radio-iodinated aromatic analogue of norepinephrine. Therefore, it is
stored and concentrated in adrenergic storage vesicles, and it has a strong affinity
for the adrenal medulla and adrenergic nerve tissue. However, unlike norepineph-
rine, it has no affinity for postsynaptic receptors, and it also cannot be metabolised
by either monoamine oxidase (MAO) or catechol-o-methyl transferase (COMT).
These peculiarities permit to identify possible abnormal masses, due to the uptake
and storage of the tracer. Prior to the imaging test, it is necessary to determine
whether the patient has previously taken drugs that could interfere with the tracer
uptake such as sympathomimetics. Furthermore, sodium or potassium perchlorate
should be administered to avoid thyroid uptake of free iodine. Bladder should be
emptied before scintigraphy. Afterwards, 123I MIBG is administered through a
peripheral venous line. At 24 and 48 h after MIBG injection, anterior and posterior
whole-body scans are performed with a gamma camera. In normal condition, at
24 h after the injection, the patient shows a remarkable activity in the urinary blad-
der, liver, heart and salivary glands. A moderate activity can be possibly identified
in the spleen, while low uptake can be seen in lungs. It is important to monitor vital
signs during MIBG injection and to perform a slow injection of the tracer, since
hypertensive crisis has been described following the displacement of norepineph-
rine from the storage granules by MIBG [5].
Fludeoxyglucose-positron emission tomography (F-18-FDG-PET) is based on
the administration of radiolabelled fluorodeoxyglucose which, once it enters tumor
cells that have an active metabolism, cannot be further metabolised, permitting the
visualisation of the tumour mass. Nowadays, new PET-tracers with specific uptake
in the sympathetic nervous system are produced (C-11-hydroxy-ephedrine; F-18-
FDOPA), even if they are currently available only in very few institutions. Even
though this technique does not comprise the administration of radiations to the
patient, its use remains isolated to those cases of discrepancy between MIBG scin-
tigraphy and morphological imaging. It also shows to be more sensitive than MIBG
scintigraphy in detecting metastatic disease [20].
As concerns the use of imaging technique in the diagnosis and characterisation of
pheochromocytoma, anatomical tumour volumes can be better determined from CT
or MRI scans; however, for tumour staging and assessment of viable tumour tissue,
MIBG scintigraphy is superior because of its high specificity related to selective
MIBG uptake in adrenal tissue, making this technique a fundamental pre-operatory
imaging tool. MIBG scintigraphy may also be important when MRI and CT are
negative, despite a strong clinical and biochemical suspicion of pheochromocytoma.
Finally, when a recurrent elevation of catecholamines is observed after surgical treat-
ment, localization of recurrence should be attempted by MIBG scintigraphy [19].
References
1. Olivieri A et al (2012) Epidemiology of congenital hypothyroidism: what can be deduced from
the Italian registry of infants with congenital hypothyroidism. J Matern Fetal Neonatal Med
2. Clerc J, Monpeyssen H, Chevalier A, Amegassi F, Rodrigue D, Leger FA, Richard B (2008)
Scintigraphic imaging of paediatric thyroid dysfunction. Horm Res 70(1):1–13
3. Clerc J (2014) Imaging the thyroid in children. Best Pract Res Clin Endocrinol Metab
28(2):203–220
4. Cassio A, Corbetta C, Antonozzi I, Calaciura F, Caruso U, Cesaretti G, Gastaldi R, Medda E,
Mosca F, Pasquini E, Salerno MC, Stoppioni V, Tonacchera M, Weber G, Olivieri A (2013) The
Italian screening program for primary congenital hypothyroidism: actions to improve screen-
ing, diagnosis, follow-up, and surveillance. J Endocrinol Invest 36(3):195–203
5. Ranke MB, Mullis PE (2003) Diagnostics of endocrine function in children and adolescents,
4th edn. Karger, Basel/New York
6. Weber G, Vigone MC, Passoni A, Odoni M, Paesano PL, Dosio F, Proverbio MC, Corbetta C,
Persani L, Chiumello G (2005) Congenital hypothyroidism with gland in situ: diagnostic re-
evaluation. Endocrinol Invest 28(6):516–522
7. Fugazzola L, Persani L, Vannucchi G, Carletto M, Mannavola D, Vigone MC, Cortinovis F,
Beccaria L, Longari V, Weber G, Beck-Peccoz P (2007) Thyroid scintigraphy and perchlorate
test after recombinant human TSH: a new tool for the differential diagnosis of congenital
hypothyroidism during infancy. Eur J Nucl Med Mol Imaging 34(9):1498–1503
8. Bahn RS, Burch HB, Cooper DS et al (2011). Hyperthyroidism and other causes of thyrotoxi-
cosis: management guidelines of the American Thyroid Association and American Association
of Clinical Endocrinologist. Endocr Pract 17(3):456–520
9. Leger J, Gelwane G, Kaguelidou F et al (2012) Positive impact of long-term antithyroid drug
treatment on the outcome of children with Graves’ disease: national long-term cohort study.
J Clin Endocrinol Metab 97(1):110–119
10. Peroni E, Vigone MC, Bonura C et al (2012) Terapia con iodio-131 nella malattia di Graves:
luci e ombre. Informer Endocrinol 20:21–25
11. Eslamy HK, Ziessman HA (2008) Parathyroid scintigraphy in patients with primary hyper-
parathyroidism: 99mTc Sestamibi SPECT and SPECT/CT. Radio Graphics 28(5)
12. Burke JF, Jacobson K, Gosain A et al (2013) Radioguided parathyroidectomy effective in
pediatric patients. J Surg Res 184:312–327
13. Parathyroid Scintigraphy. A Technologist’s Guide (2005) European Association of Nuclear
Medicine
14. Dumitrscu CE, Collins MT (2008) McCune-Albright syndrome. Orphanet J Rare Dis 3:12
15. Bousson V, Rey-Jouvin C, Laredo JD et al (2014) Fibrous dysplasia and McCune-Albright
syndrome: Imaging for positive and differential diagnoses, prognosis, and follow-up guide-
lines. Eur J Radiol 83:1828–1842
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18L-3,4 hydroxyphenylalanine positron emission tomography scanning. World J Radiol
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Horm Res 69:2–13
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congenital hyperinsulinism by 18F-Fluorodopa PET scan. J Pediatr 150(2):140–145
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cortical preservation. Indian J Pediatr 81(8):780–784
Radionuclide Studies with Bone-Seeking
Radiopharmaceuticals in Pediatric 8
Benign Bone Diseases
Diego De Palma
Contents
8.1 Introduction 139
8.2 Technique 140
8.3 Sedation 140
8.4 SPET/TC 141
8.5 Caveat and Pitfalls 142
8.6 Clinical Indications 142
8.7 Take-Home Messages 146
References 147
8.1 Introduction
Benign bone diseases are a relatively common problem in children. They can be
either congenital disorders of the bone; stable, or slowly growing, benign space-
occupying lesions; acute, symptomatic illnesses, like acute osteomyelitis, bone
infarction, and avascular necrosis; or consequences of physical activity or trauma-
tism, like “occult” or stress fractures.
Bone scintigraphy (BS) with 99mTc-MDP is used from more than 40 years for
evaluating such problems, thanks to its high sensitivity and negative predictive
value, coupled with a fast whole-body exploration [1]. These features are still
worthy, also in the MRI era, when child sedation is required for scanning. The radia-
tion burden implied can be kept below 3 mSv optimizing the administered activities
according to the EANM/SNMMI reference tables [2] and taking into account the
progress of gamma-cameras in regard to sensitivity and resolution.
D. De Palma, MD
Nuclear Medicine Unit, EANM Paediatric Committee, A.O. Circolo Hospital
and Macchi Foundation, Varese, Italy
e-mail: didepal@tin.it

DOI 10.1007/978-3-319-21371-2_8
140 D. De Palma
The appearance on the market of the hybrid SPET/CT systems simultaneously

offered new chances of single-step lesion characterization and new challenges in
performing high-quality scans without raising too high the radiation exposure [3].
The availability of 18F as a PET bone-seeking agent moreover will require in the
future a careful analysis about the advantages it can offer in respect to conventional
gamma emitting RF. The superior resolution of the system and the faster time
schedule (final images are obtained in a maximum time of 90 min.) are definite
advantages [4,5], while the need for a whole-body CT and the more likely need for
deep sedation look like drawbacks in the benign disease clinical setting; physicians
should moreover learn to read images with features different from those obtained
with diphosphonates.
8.2 Technique
The various bone-seeking RF available on the market are overall equivalent about
image quality and diagnostic yield. They adhere to bone matrix production areas
following the bone mineralization process and proportionally to its intensity but
without becoming part of the bone matrix, contrarily to fluoride. In children the
bone uptake and the consequent blood clearance are faster due to the high avidity of
the growth plates; this normally allows to obtain high-quality images also only 120–
150 min. after intravenous administration. Whole-body images should normally be
acquired independently to the localization of symptoms. For smaller children, mul-
tiple static images with large overlap are recommended, to avoid longer immobili-
zation time and for allowing, if necessary, repositioning of limbs; care must be used
in comprehending all the upper limbs into the frames.
The skull may be positioned in lateral projection, for avoiding the closeness between
the detector and the nose. The lower limbs must be positioned with the feet rotated
inward with the toes touching themselves and the calcaneus separated. This, the so-
called neutral radiographic position, allows to visualize tibia and fibula parallel and
well separated (Fig. 8.1). Thigh zooming should be avoided; the frame time should be
a trade-off between image quality and the capacity of the children to stay still.
Three-phase technique is strongly recommended, independently from the clini-
cal problem, because increases information throughput at no added irradiation cost.
Blood flow images must be aimed to the body segment most suspicious, if no radio-
logical or clinical localization is available, or otherwise targeted on the culprit site.
A 1-s framing time for a total of 90 s, 128 × 128 matrix, is adequate. Blood pool
images should encompass the whole body and may be acquired also with a rela-
tively fast (5–10 min) whole-body scan [6].
8.3 Sedation
Bone scan images are very sensitive to movement artifact. Normally children above
6 years of age are able to stay still for the time required; velcro straps, sandbags,
video, and cooperative parents normally are sufficient for younger children [7]. A
8 Radionuclide Studies with Bone-Seeking Radiopharmaceuticals in Pediatric 141
a b
Fig. 8.1 99mTc-MDP scan. (a): Whole-body anterior and posterior views of a 10-year-old male.
Left leg correctly positioned shows well-defined tibia and fibula; right leg slightly extra rotated,
due to an inflammatory lesion in the proximal tibial metaphysis, shows superimposition of the two
bones. (b) Normal multiple static whole-body scan of a 3-year-old male with good overlap of the
field of views, limbs correctly positioned. Note the faint shine-through of the costochondral junc-
tions in the chest posterior view
careful, friendly explanation of the procedure is of paramount importance in acquir-

ing child and parents’ cooperation. In babies below 15 kg, oral chloralium hydrate,
up to 50 mg/kg, at least 20 min. before the scan, may provide light sedation.
Nevertheless, every time a pharmacological intervention is necessary, this must be
performed according to the institutional guidelines and under the maximum safety
schedule [8].
8.4 SPET/TC
The birth of hybrid systems fulfilled the dream of nuclear medicine to be able to
precisely allocate RF distribution into an anatomical detailed map. Of course, when
dealing with bone diseases, the CT component of the image carries independent,
very valuable information, not hampered at all by the lack of contrast media admin-
istration. In pediatric age, on the other hand CT scan increases the radiation burden,
and the tube setting parameters must be carefully optimized to minimize this
increase, taking into account the natural high contrast of bone tissue and reducing
the scan field according to the abnormalities of uptake observed in the scintigraphic
image [9]. We must at end be aware that CT cannot solve every diagnostic problem
and sometimes it is wiser to not perform SPET/CT when the clinical context strongly
suggests the need for an MRI (Fig. 8.2).
142 D. De Palma
a b
Fig. 8.2 Three-phase bone scan of a 2.5-year-old limping female. A previous spine MRI under
sedation was normal. Blood flow phase aimed at the knee (not shown) unremarkable. Whole-body
blood pool (a, b) images showed increased blood content at the left sacroiliac joint. Bone phase (c)
confirmed the finding. SPET/CT not performed, MRI suggested for possible space-occupying
lesion. Osteoarthritis of the left sacroiliac joint confirmed thereafter
8.5 Caveat and Pitfalls
Bone-seeking RF are all actively excreted by the urinary system. Children must be
encouraged to drink or breastfeed. Every potentially contaminated dressing (diapers,
underwear, etc.) must be removed before the scan and toilet-trained children invited to
void. Injection site, especially if an intravenous stable access was used, should be
recorded, for avoiding misinterpretation. It is better to not use central venous catheters.
During the skeletal development many growth plates are visible; their location
must be known by the interpreting physician for avoiding misinterpretation. Beware
also the “shine-through” phenomenon, i.e., the visibility of a focus of uptake on
both opposite (e.g., either anterior or posterior) images.
8.6 Clinical Indications
Bone space-occupying lesions are normally detected by X-rays, serendipitously or

because of local pain [10]. They are classified according to their calcium content
and their impact on the bone integrity. Bone scan easily allows to distinguish
Fig. 8.3 A 12-year-old female with pain at the right foot. Plain X-ray film showed osteolytic
lesion of likely benign meaning (non-ossifying fibroma). SPET/CT (a MIP image, b fused selected
slices, c pure CT slices) showed high uptake on the lateral part of the lesion, suggesting cortical
painful erosion. Curettage performed
between stable lesions and growing ones, according to the intensity of the RF
uptake. Osteomas (bone islands), osteopoikylosis, simple bone cysts, non-ossifying
fibromas and enchondromas in the majority of cases show faint or unremarkable
peripheral uptake, except when they undermine the integrity of the cortex (Fig. 8.3).
Aneurismal bone cysts, fibrous dysplasia areas, osteoid osteomas and osteoblasto-
mas are characterized by increased uptake, the latter two very intense. SPET/TC is
very useful for studying these lesions and can become a “one stop shop” (Fig. 8.4)
for the detection of osteoid osteoma [11], due to the ability of detecting the nidus,
efficiently integrating the data obtained with MRI [12]. Dealing with lesions, like
fibrous dysplasia or chronic recurrent multifocal osteomyelitis (CRMO) [13], often
multiple, bone scans still represent the more efficient whole-body survey available.
Children may be affected by many forms of bone problems related to an altered
blood supply. The commonest is the femoral head avascular necrosis [14], in which
the landmark of “cold spot” of the ossification nucleus at a well-timed bone scan is
sometimes still more specific than the RM findings (Fig. 8.5). Bone infarction may
happen in children affected by malignant disease or treated with steroids, but the
condition more at risk is sickle cell disease [15]. Bone scan may help to differentiate
sickle crisis from osteomyelitis, especially when there is an involvement of ribs or
other bone, rarely affected by infection. Hybrid image is a big step forward in these
patients, because CT can show, according to the nature of the lesion, the bone
destruction of metastasis, the marrow calcium deposition of bone infarction, or
nothing at all in case of infection. The reflex sympathetic osteodystrophy can be
found in pediatric age, too (Fig. 8.6), sometimes with the uncommon feature of a
reduced blood flow.
144 D. De Palma
Fig. 8.4 (a) A 16-year-old male with pain at the right foot. Plain X-ray film reported as unremark-
able. SPET/CT (a) SPET sagittal images, (b) fused sagittal images, clearly showed high uptake at
the proximal head of the II metatarsal bone. (b) The CT section delineated the presence of a dense
lesion with radiolucent core: osteoid osteoma. Radiofrequency ablation performed
a b
Fig. 8.5 A 4.5-year-old female with sudden onset of pain at the right hip. T2-weighted MRI (a)
showed edema of the joint tissue, the femoral head, and the cranial ossification nucleus and was
reported as osteoarthritis. Bone scan (b) clearly showed no uptake into the cranial ossification
nucleus: Perthes’ disease
a d
Fig. 8.6 An 8-year-old male limping and with a painful swollen right foot. Three-phase bone scan
(a blood flow, b blood pool, c bone phase) showed reduced flow, content, and uptake in the whole
limb below the knee, due to reflex sympathetic dystrophy. T2-weighted MRI (d) showed only mild
edema of the tibial diaphysis
Bone scan is still a first-line diagnostic tool in case of suspected acute osteomy-
elitis, especially in younger children or when the localization of the site is difficult
(limping child or backache). In this clinical setting, the easier and faster whole-body
exploration often favorably compare with the MRI, even more when sedation is
necessary for the latter. BS at end can help in differentiating osteomyelitis from
arthritis, thanks to the possibility of evaluating the blood flow and blood pool using
the three-phase technique [16].
146 D. De Palma
a b
d c
Fig. 8.7 A 16-year-old male soccer player, with pain at the left foot. Plain X-ray film normal,
MRI of the feet showed marrow edema of the astragalus and the scaphoid. Whole-body scan (not
shown) demonstrated uptake at the left fibula. SPET/TC (a MIP image, b fused selected slices, c
pure CT slices) localizes the uptake at the lateral part of the cortex, with cortical thickness. Stress
fracture. Careful windowing of the CT (d) images showed the faint break
The widespread diffusion of sport practice between children and teenagers defi-
nitely increased the chances of sport-related trauma [17]. Besides overt problems,
there may be more subtle lesions (typically stress fractures), very difficult to reveal
especially when the spine, hands, or feet are involved. The youngster often com-
plains of only a mild, chronic pain, sometimes denied if an important competition is
approaching. Bone uptake increases rapidly and clearly after such a damage, and BS
is then extremely sensitive in localizing the site of the problem; more, if an addi-
tional hybrid scan is acquired targeted at the site revealed by the RF distribution, the
evaluation of the CT images can be efficiently driven (Fig. 8.7). BS is also valuable
in cases of suspect child abuse [18].
8.7 Take-Home Messages
BS still plays a role in evaluating benign bone disease. Its high-sensitivity fast
whole-body scanning and the availability of blood flow and blood pool information
with the three-phase technique are very valuable tools. Hybrid images integrate in a
single image and imaging session RF and CT information, enhancing their respec-
tive diagnostic yield. Neither can match the tissue contrast and resolution of the
MRI, mandatory every time a likely malignant lesion is suspected. The relative
management impact of radiation burden and sedation should be weighed case by
case.
References
1. Nadel HR (2007) Bone scan update. Semin Nucl Med 37(5):332–339
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Nuclear Medicine in Pediatric
Gastrointestinal Diseases 9
Angelina Cistaro and Michela Massollo
Contents
9.1 Ectopic Gastric Mucosa in Meckel’s Diverticulum 150
9.2 Inflammatory Bowel Diseases 151
9.3 Appendicitis 153
9.4 Gastroesophageal Reflux and Esophageal Transit 156
9.4.1 Gastroesophageal Reflux 156
9.4.2 Esophageal Transit 156
9.4.3 Gastric Emptying 157
9.5 Hepatobiliary Scintigraphy 158
9.6 Hyperinsulinism 161
9.7 Protein-Losing Enteropathy 161
9.8 Colonic Transit 162
9.9 Gastrointestinal Bleeding 163
9.10 Hepatoblastoma 164
References 165
A. Cistaro (*)
Positron Emission Tomography Centre, IRMET S.p.A., Euromedic Int., V.O. Vigliani 89, 10100,
Turin, Italy
Chief of PET Pediatric AIMN Inter Group, Turin, Italy
Department of Nuclear Medicine, Institute of Cognitive Sciences and Technologies, National
Research Council, Rome, Italy
e-mail: a.cistaro@irmet.com
M. Massollo
Department of Nuclear Medicine, Galliera Hospital, Mura delle Cappuccine 14, 10100,
Genoa, Italy

DOI 10.1007/978-3-319-21371-2_9
150 A. Cistaro and M. Massollo
9.1 Ectopic Gastric Mucosa in Meckel’s Diverticulum
Gastrointestinal bleeding in pediatric patients can be suspected for the presence of

Meckel’s diverticulum (MD) that is caused by an incomplete closure of the ompha-
lomesenteric duct and more frequently located in the ileum about 50–80 cm from
the ileocecal valve. It occurs in 1–3 % of the population, more common in male
patients. The ectopic gastric mucosa present in the diverticulum may result in muco-
sal damage and bleeding due to the production of acid and pepsin [1].
Scintigraphy with 99mTc-pertechnetate is an important and noninvasive test with
a low radiation burden and it is easy to perform. In particular, it has a high accuracy
for the detection of MD with ectopic gastric mucosa [2]. It is used to localize ecto-
pic gastric mucosa in an MD [3, 4], due to the capacity of this tracer to avidly accu-
mulate in gastric mucosa and then to reveal ectopic gastric mucosa in the
diverticulum. The test represents still today the most accurate noninvasive technique
for identifying ectopic gastric mucosa in Meckel’s diverticulum, with high specific-
ity and positive predictive value (close to 100 %) both in children and in adults [5,
6]. False-negative results may be due to barium enema, upper GI examination,
recent in vivo RBC labeling, or again anatomic causes of error, such as small amount
of gastric mucosa in Meckel’s diverticulum, ischemia, or necrosis, or obscured by
urinary tract activity (e.g., bladder) [3]. Moreover, false-positive result may be
related to laxatives or endoscopy causing bowel irritation, urinary tract activity,
lesions with increased blood pool, ulceration, inflammation, irritation, tumor, or
intussusception.
Any type of patient preparation to performing the examination is not necessary,
but it is important [3] to determine whether the patient has had recent in vivo RBC
labeling in which all circulating RBCs were treated with stannous ion by intravenous
administration of a “cold” pyrophosphate kit. If so, Meckel’s scan may be compro-
mised, because intravenous 99mTc-pertechnetate will label RBCs rather than concen-
trate in ectopic gastric mucosa. This may occur for days after the administration of
stannous pyrophosphate. This is not a problem with in vitro labeling procedure.
The procedure requires an intravenous injection of 3.7 MBq/kg of body weight
of 99mTc-pertechnetate and subsequent serial images of the abdomen, acquired for at
least 30 min in the anterior view. A camera with large field of view is preferred and
a collimator with a low-energy, all-purpose, parallel hole (photopeak, typically
20 % window at 140 keV; computer, 128 × 128 matrix, single- or two-byte mode).
The left lateral decubitus position during the acquisition time can decrease small
bowel activity arising from the stomach, increasing the diagnostic accuracy.
The images may be summed to make multiple sets of 10–15 min each, to facili-
tate interpretation of the data. Additional static images at the end of the dynamic
series, as SPECT acquisition, can highly aid the identification of Meckel’s diver-
ticulum [7].
A positive scan demonstrates the appearance of focal activity in the ectopic gas-
tric mucosa at the same time as in the normal gastric mucosa, although a small
Meckel’s diverticulum may appear later than the stomach. The most frequently ana-
tomic position where it may be displayed is the right lower quadrant. The anatomic
sites that most often can be misinterpreted to be the diverticulum are the kidneys
9 Nuclear Medicine in Pediatric Gastrointestinal Diseases 151
and the ureter or the bladder, in which there is an activity that, however, usually
appears after that is seen in the normal gastric mucosa.
Some pharmacologic maneuvers have been reported to improve the detection of
Meckel’s diverticulum, for example, the use of pentagastrin, histamine H2 blockers,
or glucagon [3]. Pentagastrin is a potent stimulator of gastric secretions and increases
gastric mucosa uptake of pertechnetate and also stimulates the secretion of pertech-
netate and GI motility, potentially reducing ectopic site activity. Histamine H2
blockers (cimetidine, ranitidine) block secretion from the cells and increase gastric
mucosa uptake. Glucagon relaxes the smooth muscles of the GI tract, decreasing
peristalsis. However studies with pentagastrin, histamine-H2 blockers, or glucagon
are rarely performed [8], because pharmacologic pretreatment is not considered
necessary for obtaining a high-quality Meckel’s scan [3].
9.2 Inflammatory Bowel Diseases
Inflammatory bowel diseases (IBD) are diseases that often debut in late childhood
or adolescence and include two different clinical entities causing chronic inflamma-
tion of the intestines, ulcerative colitis and Crohn’s disease, that are chronic but
characterized by alternating periods of relapse and remission [9].
Due to the continuous exacerbations of the disease, it is crucial to have a reliable
and easily reproducible diagnostic test. However the endoscopic methods are inva-
sive and require sedation, involving some risks, and often can only evaluate a lim-
ited portion of the colon. In addition, often there is a poor correlation between
clinical symptoms and endoscopic [10–12] or histological findings, and, finally
[13–15], the endoscopic findings cannot predict the response to the treatment [10–
12, 14].
Autologous leukocytes labeled with 99mTc-hexamethylpropyleneamine oxime
(HMPAO) is used to characterize active IBD [16–19]. The pathophysiologic basis
of its use is correlated to the recruitment of the circulating leukocytes at the site of
inflammation through a multistep process: adhesion to microvascular endothelium,
transmigration through the vessel wall, and further migration in extravascular tissue
and into the bowel lumen [20].
The diagnostic accuracy of 99mTc-HMPAO leukocyte scintigraphy in IBD is high,
with sensitivity and specificity around 90 % [21]. It may be stated that a negative
leukocyte scan virtually excludes the presence of active disease and the sensitivity
of the method in untreated patients is high even in the early stages of disease, when
radiologic or endoscopic findings are often normal or equivocal.
The labeling of leukocytes with 99mTc-HMPAO with 20–45 mL of venous blood
has been described [16].
Two to 3 h after injection, and no later, an 8 min static anterior supine view of the
abdomen and pelvis is obtained, followed by SPECT imaging to provide better
localization of disease distribution [22].
A large field of view gamma camera with a low-energy, high-resolution collima-
tor is usually preferred. Early imaging of the pelvis and abdomen is essential (bowel
activity is seen in 20–30 % of children by 1 h and 2–6 % of adults by 3–4 h
postinjection). Regional images are obtained for at least 800,000 counts/large field of
view of 5–10 min/view. Whole-body images should include the anterior and poste-
rior head, chest, abdomen, pelvis, and extremities when clinically indicated. A lim-
ited study to evaluate a particular region of the body is acceptable in select cases.
SPECT images of the chest, abdomen/pelvis, or spine may be helpful [23]. Accurate
interpretation of labeled leukocyte scintigraphy requires knowledge of the normal
and abnormal variants of leukocyte localization in the abdomen. Abnormal bowel
localization may be seen by 15–30 min and usually increases in intensity over the
next 2–3 h. The degree and extent of bowel disease are usually demonstrated by
1–2 h. Shifting patterns of bowel activity on later images usually indicate distal tran-
sit of labeled granulocytes or, at times, bleeding within the bowel lumen. False-
positive results can occur from rapid small bowel transit of hepatobiliary secretion
and focal accumulation of activity in the cecum, particularly if imaging is done after
1 h in children or 4 h in adults. Active gastrointestinal bleeding or swallowed cells
can be mistaken for an inflammatory bowel process. Focal collections of inflamed
peritoneal fluid or sites of focal bowel inflammation can be mistaken for abscess
[23]. Volume-rendered images using the maximum-activity-projection or maximum-
intensity-projection technique also are derived from the SPECT data in order to
increase continuity of structures and facilitate comprehension of spatial relationships
[24].
Although leukocyte imaging is useful, PET with 18F-FDG is becoming the new
standard for nuclear medicine imaging in patients with IBD, based on the known
potentiality of this tracer to localize the inflammatory lesions [9, 25, 26]. 18F-FDG
has been proposed for imaging [31] infection/inflammation in part because it has
been seen at sites of infection/inflammation during routine 18F-FDG imaging of
cancer patients. Further studies showed that cells involved in infection and inflam-
mation, especially neutrophils and the monocyte/macrophage family, are able to
express high levels of glucose transporters, especially GLUT1 and GLUT3, and
hexokinase activity [25, 32–35].
From limited experimental studies, it seems that the ability of the procedure to
identify sites of inflammation and infection is related to the glycolytic activity of the
cells involved in the inflammatory response. Many types of cells are involved in this
process although no single cell was found specifically and consistently involved in
all models. In addition, enhanced glucose consumption and subsequent 18F-FDG
uptake can also be the result of a stress reaction of the affected cells in response to
cell damage (metabolic flare) [36].
For this reasons, 18F-FDG PET and PET/CT have been proposed as noninvasive
imaging methods to assess extent, location, and disease activity in adult and pediat-
ric patients with IBD [9, 27, 28].
The diagnostic performance of 18F-FDG PET has proven to be excellent, with
studies on pediatric patients where the average sensitivity was 98 % (higher than
both endoscopy and abdominal ultrasound) and overall accuracy was comparable to
the invasive procedure (83 % vs. 82 %) [25, 26]. Considering also that this technique
avoids the long preparation times and the risks of radiolabeled autologous leuko-
cytes, 18F-FDG PET may offer a definite clinical advantage for the patients [29].
Even if 18F-FDG PET/CT may not be able to replace conventional studies, this
functional method may be useful when conventional studies cannot be performed or
fail to be completed [30].
Patients must fast for at least 4 h before 18F-FDG imaging, during which time
they should be encouraged to drink sufficient water to ensure hydration and promote
diuresis. Necessary medications are allowed and must be recorded.
Because the effect of antibiotics on 18F-FDG uptake is unknown, it is useful to
avoid such drugs, but no general recommendation on withdrawal can be stated. The
patient should be advised to avoid strenuous physical exercise within 24 h before
injection.
18F-FDG dose to obtain good imaging with a PET scanner operated in three-
dimensional mode is optimized according to the EANM pediatric dosage card
issued in 2008 [37].
With the current PET/CT scanners, the acquisition is performed in 3D whole-
body mode, using steps of 1.5–3 min per bed position. Whole-body acquisition is
usually defined as a field of view covering the head to mid thigh, starting in the
pelvic area, when the bladder is empty.
In conclusion, 18F-FDG PET may be useful when endoscopic evaluation may
not be feasible. In patients with an established diagnosis of IBD, 18F-FDG PET and
PET/CT may provide information about disease activity, location, and extent within
the intestinal tract, allowing early recognition of disease relapse and possible com-
plications of the disease in association with clinical symptoms, physical exam, and
laboratory data. 18F-FDG PET and PET/CT may guide decisions regarding the
choice of therapy and may also allow the evaluation of efficacy of the medical ther-
apy in IBD, because metabolic changes after the treatment (assessed by 18F-FDG
PET) usually precede morphological changes assessed by conventional imaging
methods (Figs. 9.1 and 9.2) [38, 39].
9.3 Appendicitis
Acute appendicitis is a surgical disease, particularly difficult to diagnosis in chil-

dren. Delay in diagnosis is associated with morbidity from perforation, abscess,
and peritonitis. It is therefore incumbent for the management of the pediatric
patients with abdominal pain to correctly diagnose in order to treat patients
appropriately.
In particular, in patients with abdominal pain and atypical or equivocal signs,
symptoms, or laboratory tests, adjunctive imaging studies often are used to increase
early diagnostic accuracy. Other than abdominal x-rays, ultrasound probably is the
most commonly used adjunctive test for the patient with an atypical presentation.
However, it has an accuracy of only 30 % in patients with early appendicitis because
the appendix may not display the changes required for visualization [40].
99m
Tc-HMPAO-labeled leukocyte imaging is highly sensitive for detecting even
small inflammatory processes in the abdomen because of high target-to-background
ratio and early rapid uptake at sites of inflammation [41]. In fact, 99mTc-HMPAO is
Fig. 9.1 A 16-year-old

boy with Crohn’s disease.
The maximum-intensity-
projection 18F-FDG-PET
image shows a diffuse and
intense radiopharmaceutical
uptake in the large bowel
an agent that complexes avidly with polymorphonuclear leukocytes, and it has a

rapid uptake into areas of acute inflammation [42, 43].
An anterior image of the pelvis has to be acquired at 30–60 min postinjection,
and it needs to be repeated at approximately 60 min intervals until either the scan
showed abnormal uptake, indicating a positive scan, or remained negative until 3 h,
at which time scanning was terminated.
There are a variety of abdominopelvic inflammatory processes that may be
detected with 99mTc-WBC imaging, for example, inflammatory bowel disease,
Fig. 9.2 The same patient in Fig. 9.1; 1 year later, posttreatment maximum-intensity-projection
18F-FDG-PET image shows a complete disappearance of any radiopharmaceutical uptake in the
large bowel
abscess, and even bowel ischemia, and often differentiating between these condi-
tions and appendicitis is not easy to obtain, and this results in a specificity of 85 %
[16]. However, this issue can be obviated if the positive scans are interpreted in light
of the overall clinical picture in order to consider 99mTc-HMPAO WBC imaging as
an accurate, noninvasive test to exclude appendicitis in children with clinical suspi-
cion of the disease but with anomalous presentation.
It is noted that inflammatory lesions show an avid uptake of 18F-FDG. The high
resolution of PET, especially associated to CT or MR, together with the high con-
centration of 18F-FDG in inflammatory tissues, makes PET a potential useful tool
for an earlier diagnosis of appendicitis and other abdominal inflammatory diseases.
However, the use of 18F-FDG-PET in the detection of appendicitis is rare. More
often, it is an incidental finding of high 18F-FDG uptake in the right iliac fossa due
to appendicitis during exams performed for malignancies. Familiarity with the nor-
mal pattern and physiologic variations of 18F-FDG distribution and with clinical
data relevant to the patient can direct to a correct diagnosis, reducing a misleading
differential diagnosis with tumors [44, 45].
9.4 Gastroesophageal Reflux and Esophageal Transit
Radionuclide studies for evaluating gastrointestinal transit in adults have been

adapted for use in infants and children for assessing esophageal transit, gastro-
esophageal reflux, and gastric emptying.
9.4.1 Gastroesophageal Reflux
Gastroesophageal reflux, which is a condition characterized by the reflux of gastric

and duodenal contents across the gastroesophageal junction into the esophagus, can
occur in infants typically from 2 months of age. Typically, children can have symp-
tom resolution by 18 months of age, and 30 % of them may have symptoms until the
age of 4 years. The presence of gastroesophageal reflux may be related to severe
complications, as strictures and pneumonia [46].
To provide information about esophageal and gastroesophageal function, nuclear
medicine technique may be relevant with esophageal and gastroesophageal
scintigraphy.
99m
Tc-sulfur colloid is often used for the assessment of gastroesophageal reflux
in children, and the tracer should be added to two thirds of the feeding volume typi-
cal for the patient, with a dose of 0.1–1 mCi (3.7–37.0 MBq), in order to leave one
third unlabeled to clear any remaining activity from the oropharynx and esophagus
[47–49].
Gastroesophageal scintigraphy is best performed at the time of a usual feeding.
Then, short-lasting 5 s anterior dynamic images are acquired for 60 min, and at the
end, anterior and posterior static images of the thorax can be acquired to look for
evidence of aspiration.
The dynamic images should be reviewed to recognize any episodes of reflux and
regions of interest may be placed on the entire esophagus and on the upper esopha-
gus to aid in the analysis of data and in order to demonstrate the number of episodes
of reflux and level reached within the esophagus, and the clearance rate of reflux
episodes may then be determined.
9.4.2 Esophageal Transit
Radionuclide-esophageal transit studies have been performed in infants, usually as

part of the evaluation for reflux or in the evaluation of patients with esophageal
motility disorders such as achalasia, diffuse esophageal spasm, nutcracker esopha-

gus, tracheoesophageal fistula, Down syndrome, esophagitis, systemic sclerosis,
and diabetes mellitus.
Other diagnostic methods, as esophageal manometry, contrast radiography, and
endoscopy, may be used to assess esophageal peristalsis, anatomical lesions, and
mucosal lesions, but the advantages of esophageal scintigraphy include its noninva-
sive nature, quantifiability, and low radiation burden. Its clinical application has
been suggested to be useful when the other procedures are unavailable or not toler-
ated by the patient or when the results are equivocal [49–55].
A 10 mL bolus of water or milk labeled with 150 μCi (5.55 MBq) of 99mTc-sulfur
colloid is administered to the patient in the supine position. Posterior images at 0.4 s
intervals for 150 frames are acquired, including the mouth and stomach, in the cam-
era field of view. A radioactive bolus is placed in the mouth and swallowed on com-
mand followed by a dry swallow 30 s later. Abnormal studies may be repeated in the
upright position to determine the effect of gravity.
Image analysis is performed by the evaluation of time activity curves derived
from regions of interest placed on the upper, middle, and lower thirds of the esopha-
gus and on the stomach. This procedure may demonstrate abnormal esophageal
transit in pathologic states and may also visualize esophageal transit condensing
dynamic images.
Usually, the normal transit time through the esophagus is typically less than 10 s.
Esophageal transit ranges from 3.4 ± 1 s for infants to 4.6 ± 1.9 s for patients 8–16
years of age. Gastroesophageal reflux and esophagitis are associated with prolonged
transit times [56].
9.4.3 Gastric Emptying
Patients with abnormal gastric emptying may present nausea, vomiting, abdominal
discomfort, early satiety, diarrhea, and “dumping.”
The correct assessment of gastric emptying helps to guide treatment decisions,
particularly in the neurologically impaired children that frequently demonstrate
symptomatic delayed gastrointestinal motility.
Furthermore, delayed gastric emptying may be secondary to several pathological
conditions, as pyloric or duodenal stenosis, acidosis, hypothyroidism, autonomic
neuropathy associated with diabetes mellitus, central nervous system disease, sys-
temic lupus erythematosus, dermatomyositis/polymyositis, infection, and many
others.
The rate of gastric emptying assessed scintigraphically has been shown to depend
on the type of meal used: liquids typically empty faster than solids.
In infants, a milk or formula feeding is usually administered and the type of milk
and volume fed should be standardized according to patient size. However, many of
the patients studied have feeding difficulties and in these cases is difficult to stan-
dardize the volume fed.
The dose of 99mTc-sulfur colloid added to the milk depends on whether gastric
emptying is performed in conjunction with the reflux study.
If only the rate of emptying is of interest, this dose can be decreased to 100 μCi
(3.7 MBq).
In older children, solid gastric emptying may be performed by having the patient
eat an egg sandwich containing 99mTc-sulfur colloid (250–300 μCi). The meal
should be scaled according to patient size (where adults are given 4 eggs and 50 mL
of water). Thirty second anterior images are acquired every 10 min. Between
images, the patient should sit upright. Images are acquired until 120 min.
A region of interest is drawn around the stomach. Activity from the bowel should
not be included in the region of interest.
The range for normal gastric emptying has been difficult to establish in children
for ethical reasons. Furthermore, the test meals have not been standardized. In gen-
eral, laboratories have to decide on the values to be used based on their own experi-
ence. A study performed several years ago in children thought to be normal
retrospectively shown, for milk, a residual of 36–68 % at 60 min and 42–56 % in a
small number of older children [57].
In another report using dextrose as the test meal, the 60 min residual was 27–81 %
in children under 2 years of age and 11–47 % in older children. This age-related
difference in emptying rate has been observed by others, although the composition
of the meal may also play a role [58].
9.5 Hepatobiliary Scintigraphy
Hepatobiliary scintigraphy is useful in the assessment of patients with right upper

quadrant pain, in particular if there is the suspicion of acute cholecystitis.
Cholecystitis is less common in children than in adults, but its incidence in pediatric
patients has probably been underestimated [59, 60].
It is possible to recognize two types of cholecystitis: acute calculous cholecysti-
tis, which occurs when the cystic duct becomes obstructed by gallstones leading to
gallbladder distension and edema, and acalculous cholecystitis, which can occur in
prolonged illness, sepsis, or trauma.
Both of these conditions may be associated with inflammation and edema and
consequently with blood flow impairment and bacterial infection advancement.
Typically, the most common symptoms in children are abdominal pain localized
in the right upper quadrant or epigastric region. Other symptoms include nausea,
vomiting, anorexia, and fever for several days.
The most common clinical signs are represented by a right upper quadrant ten-
derness, jaundice, and enlarged and palpable gallbladder. Regarding the laboratory
tests, leukocytosis is a common finding [61–63]. In the diagnosis of cholecystitis,
ultrasound is basic in the evaluation of the biliary tract and detecting gallstones;
however, its diagnostic accuracy presents a substantial margin of error. In a recent
systematic review of different imaging modalities in patients with suspected acute
cholecystitis [64], hepatobiliary scintigraphy is the most accurate diagnostic
imaging modality for acute cholecystitis, with a sensitivity and specificity for hepa-
tobiliary scintigraphy of 96 % and 90 %, respectively. The sensitivity of hepatobili-
ary scintigraphy results significantly higher than ultrasound (81 %).
99m
Tc-disofenin or 99mTc-mebrofenin is administered intravenously, with a dose
for infants and children of 1.85 MBq/kg (0.05 mCi/kg). Mebrofenin is always pre-
ferred in jaundiced infants with hyperbilirubinemia, with a minimum administered
activity of 37 MBq (1.0 mCi), as up to 24 h delayed images are often required. The
patient should be fasting for 4 h prior to the test. Immediately after the injection,
dynamic imaging is acquired for 60 min (0.5–1 min/frame) in anterior projects
using preferably a high-resolution collimator and 128 × 128 matrix. Additional
views such as right lateral and left or right anterior oblique may be performed, if
required. When acute cholecystitis is suspected and the gallbladder is not seen
within 60 min, delayed images for up to 4 h should be obtained [65].
In adult patients, acute cholecystitis is associated with non-visualization of the
gallbladder on hepatobiliary scintigraphy, and the visualization of gallbladder activ-
ity excludes the diagnosis of acute cholecystitis with high accuracy. However, in
children, the presence of cholecystitis is not entirely excluded if there is gallbladder
visualization, because this is possible in acalculous cholecystitis [46]. After 60 min
images, if the gallbladder is visualized, it is possible to perform additional dynamic
imaging for 60 min following infusion of 0.02 μg/kg sincalide, a synthetic C-terminal
octapeptide of cholecystokinin. Poor contraction and emptying of the gallbladder
following sincalide may occur in partial cystic duct obstruction, acalculous chole-
cystitis, or chronic cholecystitis.
Hepatobiliary scintigraphy in children can also be used for the evaluation of
choledochal cyst and biliary leak. Biliary atresia is characterized by obliteration or
discontinuity of the extrahepatic biliary system, resulting in obstruction of bile flow
[66]. The disorder represents the most common surgically treatable cause of cho-
lestasis encountered during the newborn period. If not surgically corrected, second-
ary biliary cirrhosis invariably results. In infants, hepatobiliary scintigraphy is used
to differentiate biliary atresia from hepatocellular disease [67]. The disorder, if not
surgically corrected, results in secondary biliary cirrhosis. Thus early diagnosis of
biliary atresia remains imperative, and the gold standard within the diagnostic
modalities is liver biopsy and/or intraoperative cholangiogram. Studies have dem-
onstrated 100 % sensitivity of 99mTc-mebrofenin hepatobiliary scintigraphy (HIDA
scan) for picking up biliary atresia, and its specificity has been reported to range
from 88.6 to 92 % [68, 69].
The premedication with phenobarbital or ursodeoxycholic acid before hepatobi-
liary scintigraphy may increase bile secretion and improves the diagnostic differen-
tiation between biliary atresia and neonatal hepatitis [65]. The administered activity
for infants and children is 1.8 MBq/kg (0.05 mCi/kg), with a minimum adminis-
tered activity of 18.5 MBq (0.5 mCi). Mebrofenin is always preferred in neonates
with hyperbilirubinemia, with a minimum administered activity of 37 MBq
(1.0 mCi), as up to 24 h delayed images are often necessary [67].
For the image acquisition [67], a large-field-of-view γ-camera equipped with a
low-energy all-purpose or high-resolution collimator is recommended. Whenever
possible, continuous (dynamic) computer acquisition (usually in the anterior or left

anterior oblique view) should be performed (1 frame/min). The image matrix of 128
by 128 is optimal on a standard large-field-of-view camera. In pediatric patients, an
appropriate electronic acquisition zoom should be used. Initial images are usually
acquired dynamically, starting at injection and continuing for 60 min. When visual-
ization of the gallbladder is the end point of the study, it can be stopped earlier when
activity is seen in the gallbladder. Additional views (e.g., right lateral, left or right
anterior oblique) may be obtained as needed to clarify anatomy. To resolve concern
about common bile duct obstruction (highly unlikely in the presence of gallbladder
visualization), demonstration of tracer activity in the small bowel may need to be
pursued.
The digital data can be reformatted to 4 to 6 min images for filming or digital
display. Cinematic display of the data may reveal additional information not readily
apparent on reformatted display. Image intensity scaling should be study relative
rather than individual frame relative. The former allows for appreciation of activity
changes over the duration of the study.
If there is visualization of the biliary drainage of the radiotracer into the bowel,
scintigraphy can exclude the presence of biliary atresia. If no bowel activity is
detected up to 24 h and liver uptake is normal, the diagnosis of biliary atresia is
suspected [46, 67]. If the patient is being studied for a biliary leak, 2 to 4 h delayed
imaging (or longer delays in some cases) and patient-positioning maneuvers (e.g.,
decubitus views) may be helpful. Any drainage bags should be included in the field
of view if the biliary origin of a leak or fistula is in question. In patients with a sus-
pected leak, it may be helpful to acquire simultaneous right lateral or other views on
a multihead camera.
However, normal liver uptake of tracer with no excretion up to 24 h can occur in
severe cases of neonatal hepatitis, Alagille syndrome, dehydration, sepsis, TPN cho-
lestasis, and bile plug syndrome in cystic fibrosis. Neonatal hepatitis typically demon-
strates reduced hepatocyte uptake and delayed hepatobiliary transit of tracer into the
bowel [46]. Failure of tracer to enter the gut is consistent with biliary atresia but can
also be caused by hepatocellular disease or immature intrahepatic transport mecha-
nisms. Renal or urinary excretion of the tracer (especially in a diaper) may be con-
fused with bowel activity and is a potential source of erroneous interpretation [67].
An interesting application of 18F-FDG PET in this setting is its use in children
with biliary cirrhosis and fever of unknown origin (FUO) on the waiting list for liver
transplantation. Infection imaging with FDG-PET relies on the fact that granulocytes
and mononuclear cells use glucose as an energy source specifically during their met-
abolic burst upon activation by triggers. The advantages of FDG-PET are early imag-
ing after injection, higher resolution and higher target-to-background ratio, sensitivity
to chronic low-grade infections, and high interobserver agreement [70].
Systemic infections are considered to be contraindications for liver transplanta-
tion; however, hepatic infections are frequently only cured by the removal of the
infected organ during transplantation. Therefore the information obtained by FDG-
PET imaging to identify intrahepatic infections may be crucial for the management
of patients with FUO awaiting liver transplantation [71].
9.6 Hyperinsulinism
Congenital hyperinsulinism (CHI) is a rare disease of hypoglycemia due to

dysregulated and excessive insulin secretion, with an incidence of severe cases
estimated at 1:50,000 and the incidence rising in consanguineous populations
[72, 73].
In infants, the treatment of congenital hyperinsulinism is required to prevent
possible neurologic complications. Forty percent of cases of hyperinsulinism in
children results from pathologic adenomatous pancreatic β-cells. Diffuse hyper-
insulinism involves the whole pancreas with enlarged abnormal β-cell nuclei.
Ten percent of cases of infantile hyperinsulinism are atypical and fit neither clas-
sification. Focal hyperinsulinism is cured by resection of the adenoma, whereas
diffuse pancreatic involvement may be treated with subtotal pancreatectomy.
[74, 75].
Positron emission tomography (PET) using 6-L-(18)F-fluorodihydroxyphenylalanine
((18)F-DOPA) may be useful for classifying pancreatic involvement in infantile hyper-
insulinism as focal or diffuse and can be used preoperatively to identify the two forms
of infantile hyperinsulinism, differentiating between patients who should receive cura-
tive focal pancreatic resection and those who should receive medical management
[76, 77]. (18)F-DOPA is a radioactive isotope of L-dihydroxyphenylalanine (L-DOPA),
an intermediate in the catecholamine synthesis pathway. L-DOPA is avidly taken up by
neuroendocrine cells, including CHIb-cells, while uptake is minimal in the normal
pancreas. It is not understood why CHI pancreatic tissues exhibit more a differential
uptake and retention pattern than normal tissue, particularly as CHI is not apparently
linked with altered catecholamine metabolism.
Initial observations showed a high sensitivity (88–94 %) and specificity (100 %)
of (18)F-DOPA PET imaging in differentiating focal from diffuse CHI [78, 79]
which was further enhanced by the concurrent use of CT angiography using iodine-
based dyes. The latter is useful to localize the site of the lesion, in relation to ana-
tomical structures, which is particularly useful at the time of focal lesionectomy.
Although meta-analyses of (18)F-DOPA PET imaging studies indicate good diag-
nostic performance [80, 81], recent studies have suggested that the predictive value
of scanning may not be as accurate as initially estimated [82, 83].
9.7 Protein-Losing Enteropathy
Protein-losing enteropathy can be the result of primary intestinal lymphangiectasia

or secondary intestinal lymphangiectasia in association with cardiac diseases or
obstructed lymphatics. Abnormal or inflamed mucosal surface secondary to intesti-
nal inflammation/infection and immunologic, inflammatory, and vasculitic disor-
ders can also cause enteric protein loss [84].
This pathophysiologic condition generally results from an abnormal mucosal
permeability, desquamation, inflammation, or back pressure in the intestinal lym-
phatic network [85].
The protein loss is nonselective and includes plasma proteins such as albumin, glob-
ulins, and transferrin. Radiolabeled proteins that have been used for determining enteric
protein loss include 131I-albumin, 51Cr-albumin, and 67Cu-ceruloplasmin [84].
99m
Tc-human serum albumin (HSA) has been successful in localizing the site of
enteric protein loss in adults [86–92]; however, the literature is lacking concerning
pediatric patients [93–95].
A study performed on children [96] reported that the scan has a higher sensitivity
in patients with lower albumin and total protein values, presumably reflecting a
higher rate of protein loss; they submitted all patients to an anterior abdominal scin-
tigraphy after the intravenous injection of freshly prepared 99mTc-HAS. The admin-
istered age-adjusted doses were 185–503 MBq based on an adult dose of 740 MBq.
They acquired dynamic images every minute for 1 h, using an all-purpose collima-
tor and a large-field-of-view γ-camera. Additional delayed images were obtained at
2–6 h in most patients and 24 h in a few patients.
They found enteric 99mTc-HSA uptake in 67 % of the children, suggesting the site
of protein loss. The location of the uptake was most likely in the small bowel in
91 % of the early images and in 27 % of the delayed images. Colonic activity was
noted in 72 % of the delayed images, most likely representing transit of activity
rather than a second site of protein loss.
9.8 Colonic Transit
Two different types of chronic functional constipation have been identified in chil-
dren based on colonic transit time measurement: a more generalized and severe
form known as slow transit constipation and a segmental type known as functional
fecal retention [97].
Both entities present with similar symptomatology but involve different patho-
physiological mechanisms and require different treatment strategies.
It has been shown that children thus classified respond to different treatment
strategies. Only a small proportion of cases require surgical intervention such as
appendicostomy, colostomy, or colonic resection [99–101]. The different types of
abnormal colonic transit can be identified using radiopaque markers: slow transit
(pancolonic or globalized delay), normal transit, and functional fecal retention (out-
let obstruction or distal obstruction) [98]. Colonic transit scintigraphy can aid in the
identification and therapeutic decision-making in patients with functional fecal
retention, the most common cause of chronic constipation in children [102].
This method has been used to determine colonic transit in adults with chronic con-
stipation, and the reported advantages, compared with radiopaque marker studies,
include a low radiation dose and the acquisition of multiple images allowing estimates
of gastric, small bowel, and segmental colonic transit to be made [103, 104].
Intake of laxatives has to be stopped 5 days before the transit studies, and fast-
ing is required for 4 h before the start of the test. The radiopharmaceutical 99mTc-
calcium phytate colloid, suspended in 20 mL of milk, can be administered by
mouth. The dose is determined according to each patient’s weight and is based
on an adult dose of 250 MBq. Anterior and posterior view images are obtained
immediately after ingestion and during the subsequent 2 h to estimate gastric
emptying. Three categories of colonic transit could be readily distinguished by
visual assessment of the acquired images. In studies considered to demonstrate
normal transit, the tracer reached the cecum by 6 h, passed through the colon,
and was largely excreted by 48 h. Slow transit was identified when the tracer
reached the cecum at 6 h, but most radioactivity was retained in the proximal
colon and transverse colon at 24, 30, and 48 h. Patients in whom the tracer
reached the rectosigmoid by 24–30 h but was not passed at 48 h were appreci-
ated. This pattern was defined as consistent with functional fecal retention or
outlet obstruction.
9.9 Gastrointestinal Bleeding
Gastrointestinal (GI) bleeding is often encountered in daily clinical settings.

Dramatic advances in endoscopic technology in recent years have facilitated diag-
nosis and treatment of bleeding from the esophagus, stomach, and duodenum, as
well as most cases of bleeding from the large intestine. Although it is now possible
to observe the small intestine using video capsule endoscopy and double-balloon
enteroscopy [105], diagnosing the source of GI bleeding and providing treatment
remain the challenges in some patients [106].
GI bleeding scintigraphy is a noninvasive examination that enables detection
with a bleeding rate as low as 0.1 mL/min [107]. In children, while most gastroin-
testinal bleeding may not be life threatening, it is necessary to determine the source,
degree, and possible cause of the bleeding and to distinguish minor from major
bleeding [108]. In the stable child with occult bleeding, management is geared
toward making the diagnosis and excluding more serious conditions. Investigations
are directed by the history and physical examination, but most diagnostic tests can
be performed on an outpatient basis [109].
99m
Tc-red blood cell (RBC) scintigraphy generally is useful for assessing GI
bleeding in patients. Meckel’s diverticula also may be identified through this tech-
nique, although other causes of bleeding may include intussusception, IBD, Henoch-
Schonlein purpura, gastritis, duodenitis, Mallory-Weiss tear, infectious enterocolitis,
allergic enterocolitis, midgut volvulus, polyps, tumors, vascular malformations,
enteric duplication cysts, nodular lymphoid hyperplasia, hemolytic uremic syn-
drome, and foreign body and trauma [110].
The main advantage of the use of 99mTc-RBCs is the possibility of visualization
of GI bleeding over the course of several hours. Bleeding rates as low as 0.1–0.4 mL/
min may be detected. Large bowel endoscopy of actively bleeding patients has a
low diagnostic yield and is potentially harmful to the patient, and the small bowel is
not successfully visualized endoscopically. Angiography typically localizes bleed-
ing when the rate is greater than 1 mL/min. However, for bleeding to be identified,
it should occur during the 20 to 30 s time interval during which contrast is adminis-
tered. Scintigraphy permits the visualization of the entire GI tract.
Labeling of RBCs is most efficient by the in vitro method (98 %) as compared

with the in vivo (70 %) and modified in vivo (90–95 %) methods. The disadvantage
of lower labeling efficiencies is the possibility of secretion of free pertechnetate
within the gastric mucosa into the duodenum and also the excretion of free pertech-
netate into the urinary collecting system increasing the likelihood of false-positive
studies.
Positive studies demonstrate tracer activity outside of normal vascular structures
with antegrade or retrograde motion of tracer through bowel. The motion is best
detected on cinematic display and may occur very rapidly. Small bowel bleeding
may be distinguished from a colonic source by the demonstration of rapid distal
progression through a series of multiple small, centrally located, curvilinear seg-
ments on cinematic display of the abdomen. Large bowel bleeding has a more elon-
gated pattern with peripheral location within the abdomen compared with bleeding
within small bowel. Stationary activity is more likely to represent a vascular abnor-
mality and urinary or penile activity. In rare cases, a stationary site may represent
adherent blood clot to the bowel wall.
99m
Tc-sulfur colloid also has been used in the assessment of GI bleeding. It has
the advantage of detecting rates as low as 0.05–0.1 mL/min through the achieve-
ment of a high bleeding to background ratio. Its disadvantages include a short dura-
tion of imaging time to localize bleeding of approximately 20 min and limited
interpretation of potential bleeding sites in proximity to the liver and spleen as these
structures accumulate 99mTc-sulfur colloid during the test.
Both 99mTc-RBC scintigraphy and 99mTc-sulfur colloid scintigraphy detect
sources of venous and arterial GI bleeding, whereas contrast angiography only
detects arterial sources [111–114].
9.10 Hepatoblastoma
Hepatoblastoma (HB) is the most common primary malignant hepatic tumor in

childhood [115, 116]. According to the histology, HB can be in pure epithelial and
mixed type, the latter being formed by epithelial and mesenchymal components.
The clinical onset is characterized by an abdominal mass, while in the advanced
disease, anorexia and weight loss can also be present. Ninety percent of cases pres-
ent increased level of serum alpha-fetoprotein (α-FP).
At present, complete resection is possible in more than 50 % of cases, and pre-
operative chemotherapy has been successfully used in converting unresectable to
resectable tumors [117–119]. Liver transplantation has been proposed as an option
in patients with unresectable tumors.
The follow-up is based on the association between laboratory analysis and
imaging.
In particular, although a rising level of serum α-FP is generally associated with
tumor recurrence, most protocols require additional imaging follow-up in order to
localize neoplastic lesions, as US, CT, or RM [120–122]. However, early detection
of recurrent hepatoblastoma is not always possible with conventional imaging
methods such as CT and MRI.
Fig. 9.3 A 4-year-old boy affected by hepatoblastoma. PET evaluation was performed to estab-
lish liver transplantation eligibility. Axial PET/CT fusion images show 18F-FDG-avid lesions in
the liver
A further dimension of information based on the regional biochemical and physi-

ological abnormalities can be provided by positron emission tomography (PET)
using F18-fluorodeoxyglucose (FDG), which has been successfully used for the last
two decades in localizing primary and metastatic tumors in adults [123–125]. It is
known that 18F-FDG uptake in tumors is proportional to the metabolic rate of via-
ble tumor cells, which have an increased demand for glucose than normal tissue. It
has already been proven that hepatoblastoma cells have demonstrated prominent
glycogen granules in the cytoplasm [126, 127], and this fact may suggest active
accumulation of glucose and its transformation and accumulation in glycogen gran-
ules [128] and consequently can explain the uptake of 18F-FDG.
The whole-body PET/CT scan has to be performed as a standard examination,
following the guidelines for the administered dose and for the acquisition parame-
ters of the PET imaging in pediatrics.
18F-FDG PET/CT could provide incremental diagnostic value in the initial eval-
uation of patients affected by hepatoblastoma, helping to detect additional meta-
static sites at diagnosis.
However, 18F-FDG PET/CT has no established role in the initial diagnosis of
hepatoblastoma [129], but it is helpful in detecting early recurrence [130], and few
studies have evaluated its role in follow-up and restaging of patients after chemo-
therapy and surgery [131–135].
Since experience is so far limited in the literature [136], multicenter and prospec-
tive studies are warranted to suggest the introduction of 18F-FDG-PET/CT in the
routine imaging workup for hepatoblastoma staging and in case of suspicion of
relapse (Fig. 9.3).
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Nuclear Medicine in Pediatric
Nephro-urology 10
Pier Francesco Rambaldi and Pietro Zucchetta
Contents
10.1 Clinical Context 173
10.2 Available Techniques 174
10.3 Nuclear Medicine Procedures 174
10.3.1 Dynamic Renal Scintigraphy 174
10.3.2 Static Renal Scintigraphy 177
10.3.3 Cystoscintigraphy 178
10.3.4 Clinical Informations 179
Suggested Reading 182
10.1 Clinical Context
Nuclear medicine techniques are widely used in pediatric nephrology, where treat-
ment is often based on the combined evaluation of structure and function.
The combination of functional information provided by scintigraphic studies
with morphological definition offered by traditional imaging is required in many
situations, particularly in the clinical workup of congenital hydronephrosis (HN)
and in the follow-up of vesicoureteral reflux (VUR) and upper urinary tract infec-
tions (UTI).
P.F. Rambaldi (*)

Nuclear Medicine Department, Second University of Naples, Naples, Italy
e-mail: pierfrancesco.rambaldi@unina2.it
P. Zucchetta
Nuclear Medicine Department, University Hospital of Padua, Padua, Italy

DOI 10.1007/978-3-319-21371-2_10
174 P.F. Rambaldi and P. Zucchetta
10.2 Available Techniques
Ultrasounds are the baseline examination and allow the evaluation of excretory
cavities (renal pelvis, calices, ureter) and of renal parenchyma. Moreover, it is pos-
sible to explore the urinary bladder, leaving almost no indication for pyelography.
When a better morphological definition is required, the following step is usually
MR imaging (MRI), which offers exquisite morphological detail avoiding com-
pletely ionizing radiations. However, this technique requires sedation under 5–6
years of age, and it is often difficult to access, due to the high workloads on the
scanners.
Cystography represents the mainstay for vesicoureteral reflux diagnosis.
Beside the detection and grading of reflux, it is possible to evaluate the bladder
and the urethra, which is of paramount importance in defining the nature of the
reflux. Cystosonography can offer the same informations without using ionizing
radiations, but it requires an expert operator and can be time consuming and
costly.
10.3 Nuclear Medicine Procedures
10.3.1 Dynamic Renal Scintigraphy
10.3.1.1 Radiopharmaceuticals
123
I-ortho-iodo-hippurate (123I-hippuran), 99mTc-mercaptoacetyltriglycine (MAG3),
99m
Tc-etylen-cistein (EC), and 99mTc-diethylene-triaminepentaacetic acid (DTPA)
are the most diffuse agents available for renal dynamic imaging. These radiophar-
maceuticals may be distinguished between glomerular agents (DTPA) and tubular
excreted compounds (MAG3, 123I-hippuran, EC), which are preferable in children,
due to their superior imaging characteristics.
Tubular agents allow the measurement of effective renal plasma flow (ERPF),
particularly employing 123I-hippuran. Its very favorable kinetics provides optimal
image quality, but the high cost and the short half-life of 123iodine, impacting on a
routine utilization, strongly contains its use in clinical practice. 131I-hippuran has the
same kinetic, but beta emission causes high radiation exposure and it is not well
suited to pediatric imaging.
At present, MAG3 is the most recommended agent for dynamic renal imaging in
children. Active tubular secretion determines fast intrarenal concentration, which
yields high-quality images even in smaller babies, despite the partial maturation of
renal function. 99mTc-etylen-cistein (EC) shares the same characteristics, and its use
has been described many years ago, even if it has been widely distributed in Europe
only in recent times.
DTPA is the agent most widely used for dynamic renal studies, mainly because
of its lower cost with respect to alternative radiocompounds. Its clearance rate can
10 Nuclear Medicine in Pediatric Nephro-urology 175
provide a measurement of the glomerular filtration rate (GFR), but in younger

children, the background activity is usually high and images can be difficult to
interpret.
10.3.1.2 Patient Preparation

The patient should be adequately hydrated before starting the renal scintigraphy.
Drinking water or orange juice is the best choice for older children, whereas addi-
tional feeding before starting the examination is the best way to obtain good hydra-
tion in infants.
Sedation is not necessary in the vast majority of patients, but careful planning of
the exam is essential in order to obtain good quality images without unnecessary
discomfort for the child and for the family. Detailed explanation of the procedure, a
sympathetic attitude, parents involvement, and a “child-friendly” environment are
the mainstays of a successful scintigraphic procedure.
10.3.1.3 Acquisition
Whenever possible, the child should lie supine on the collimator surface (anterior
projection is indicated only in transplanted kidneys and in rare cases of ectopy), thus
minimizing the distance from the detector and the possibility of unwanted move-
ment. Velcro strap and/or sandbags can be used to better support the patient and help
in maintaining the desired position.
The preferred matrix is 128 × 128, and it is recommended to zoom images as a
function of the body size. Frame duration should be comprised between 10 and 20 s,
and total acquisition time varies between 20 and 40 min (the longer time encom-
passes the diuretic test).
The provocative diuretic test is based on the hypothesis that the prolonged
tracer retention in a dilated but nonobstructed system depends on a reservoir
effect. Therefore, diuretic administration should determine a prompt tracer wash-
out, whereas in obstructive hydronephrosis the tracer still remains in the collect-
ing system, in the absence of a significant washout, even after bladder emptying
(Fig. 10.1).
Furosemide (1 mg/kg iv) is administered intravenously, and time of injection
should be standardized in the single laboratory, to ensure repeatability. The “clas-
sic” protocol (F+20: furosemide injection 20 min after radiopharmaceutical admin-
istration) and the “fast” protocol (F0: furosemide injection immediately after
radiopharmaceutical administration) are the most widespread options. In both cases
the acquisition has to be continued for at least 20 min after the diuretic stimulus, and
it is mandatory to acquire a post-micturition image of 1–2 min, after keeping the
patient upright for a couple of minutes (Fig. 10.2).
10.3.1.4 Processing
Images are summed for a better evaluation of morphology and parenchymal uptake.
Regions of interest (ROI) are drawn on both kidneys and on the surrounding tissue
Fig. 10.1 Female, 3 months. MAG3 diuretic renography (protocol F+2). No washout even after
micturition. Typical ascending pattern of the right renographic curve. Obstruction of the right
pyelo-ureteral junction
Fig. 10.2 Male, 7 months. MAG3 diuretic renography (protocol F+2). Slow washout during the
dynamic phase. Good washout after voiding. Indeterminate pattern of the right renographic curve.
Preserved differential renal function in the right kidney. No indication for surgery
(background) to produce background-subtracted time/activity curves and for calcu-

lation of differential renal function, expressed as percent of the renal uptake between
60 and 120 s after injection for each kidney (normal range 45–55 %). The estima-
tion of absolute clearance should be based on blood sampling, because gamma-
camera methods are plagued by many sources of error.
Excretion must be evaluated taking into account post-micturition images
because the pattern of the renogram is not reliable for a diagnosis of obstruc-
tion, even if typical obstructed and nonobstructed patterns are usually
diagnostic
Many parameters have been described for the quantitative analysis of the
excretion phase; output efficiency (OE) and normalized residual activity (NORA)
probably offer the best balance between robustness, reproducibility, and
practicability.
10.3.2 Static Renal Scintigraphy
10.3.2.1 Radiopharmaceuticals
99m
Technetium-dimercaptosuccinic acid (DMSA) is the best cortical imaging agent
available at present, presenting a very high renal uptake (45 % of the injected dose)
and low urinary excretion. Therefore, the visualization of the renal cortex, the
binding site of the tracer, is excellent, since the interfering activity in the pelvi-
calyceal system is negligible after 2–3 h from the administration.
10.3.2.2 Patient Preparation

No special preparation is required for DMSA intravenous injection, but it is
important to wait at least 2 h after injection and it is recommended to increase the
waiting time to 3 h whenever possible, to increase the quality of the acquired
images.
The child should lie on the collimator surface, using Velcro strap and/or sandbags to
maintain the required position. The mandatory views are posterior, left, and right
posterior oblique. The image should be acquired with a 256 × 256 matrix (recom-
mended minimum 128 × 128) using a zoom factor adequate to the body size (usually
between 1.5 and 2, depending on the size of the detector). Counts should be at least
300,000/image when using a parallel-hole collimator or between 100,000 and
150,000 for pin-hole collimators.
There is no consensus on the use of single photon emission tomography (SPET).
The higher image contrast could improve sensitivity for smaller cortical defects, but
it is prone to false-positive results and in most cases requires a sedation, which is not
necessary for planar DMSA scanning.
10.3.2.4 Processing
Images are evaluated preferably on a monochrome gray scale and the ROI-based
differential renal function, expressed as percentage between the two kidneys is
calculated, using the geometric mean of the counts in posterior and anterior pro-
jection. It is possible to omit the counts form the anterior projection when the
kidneys have normal morphology and dimensions and they are in normal
position.
10.3.3 Cystoscintigraphy
Radionuclide cystography is the most sensitive method to evaluate for vesicoure-

teral reflux and results in significantly less radiation exposure when compared with
conventional radiographic technique, but it cannot provide anatomical information
(e.g., on the bladder or urethra).
Direct radionuclide cystography (DRC) requires instillation of tracer (usually
99m
Tc-pertechnetate, 18–40 MBq) through a bladder catheter allowing imaging dur-
ing filling, voiding, and after voiding.
Indirect radionuclide cystography does not require catheterization, since it is per-
formed at the end of a dynamic renal scintigraphy, which requires an intravenous
injection of radio tracer. Moreover, the patient has to be able to control a voluntary
micturition.
Sterile urethral catheterization should be performed with a Foley catheter or a
feeding tube. The latter is often the preferred option, particularly in infants.
Similarly to the other nuclear medicine procedures, neither preparation nor seda-
tion is needed, but in many centers, the antimicrobial prophylaxis is considered
mandatory, to reduce the risk for catheter-induced infections.
The patient is positioned whenever possible on the collimator, taking every pre-
caution (plastic-lined absorbent paper) to prevent any contamination of the
detector.
The bladder volume can be estimated using a formula (e.g., (age in
years + 2) × 30 ml), and the corresponding volume of saline (gently warmed to 37
C) is instilled at slow rate (10 ml/min) to avoid a too fast stretching of the bladder
wall. The height of bottle should be less than 80 cm from the table. The radio-
tracer is injected in the catheter as a small bolus at the beginning of the infusion
Dynamic images are acquired in the posterior projection (matrix 128 × 128) includ-
ing kidneys, ureters and bladder in the field of view. During the filling phase the
frame rate is 5–10 s/frame and the acquisition usually ends when the calculated
volume has been instilled or the infusion stops due to back pressure. In cooperative
patients the acquisition is usually interrupted by the necessity to voiding.
During the voiding phase the frame rate is set to 2–5 s/frame and a duration of
5 min is more than adequate. The acquisition can be usually stopped after 60 s from
the start of micturition.
If a feeding tube has been used during the filling phase, it is possible to let it in
place during the voiding and to perform a second filling (cycling technique),
which is less physiologic but can enhance the sensitivity for the vesicoureteral
reflux.
10.3.3.2 Processing
Images are best evaluated in loop (cine-mode), looking for the timing and duration
of each reflux episode. It is possible to grade the reflux into three grades: mild reflux
when the tracer is seen only in the ureter; moderate when the radioactivity reaches
the collecting systems; and severe reflux when high activity is seen in a dilated ure-
ter and collecting system.
10.3.4 Clinical Informations
10.3.4.1 Diuretic Renography/Dynamic Renal Scintigraphy

Diuretic MAG3 renography plays a critical role in the diagnosis and follow-up of
pediatric hydronephrosis.
An integrated imaging approach based on the combination of ultrasonography
and MAG3 diuretic scintigraphy allows the crucial distinction between simple dila-
tation and significant obstruction with impending loss of renal function, which
demands surgical treatment.
MAG3 offers a morpho-functional evaluation of the parenchyma during the
uptake (cortical phase) and represents the most practical way for assessing differen-
tial renal function noninvasively. The outflow of the radiotracer is evaluated during
the excretory phase and in the post-voiding image, with the optional calculation of
numerical parameters (NORA or OE).
The combination of morphological data from ultrasounds (pelvic and/or calyceal
dilatation, ureter dilatation, cortical thickness, etc.) and functional scintigraphic
data identifies the kidneys at risk of functional loss and is the base for surgical man-
agement in most centers.
MAG3 renography has many other indications in pediatric nephrology, ranging
from complex urological malformations (duplex kidneys, ectopic kidneys, etc.) to
juvenile hypertension, bladder dysfunction (neurogenic bladder, myelomeningo-
cele), and kidney transplant evaluation.
10.3.4.2 Static Renal Scintigraphy

DMSA scintigraphy represents the standard for scar identification after upper uri-
nary tract infections with high sensitivity, as confirmed in animal models. It is
important to underline that for an optimal specificity, it is essential to delay DMSA
imaging at least for 6 months after the acute infection, to avoid false-positive results
related to healing parenchyma.
It is largely superior to ultrasounds in scar detection and allows an evaluation of

differential renal function, which is a critical parameter in assessing the evolution of
recurrent UTI, where kidney parenchymal damage is a critical factor in treatment
planning. DMSA scanning has an optimal sensitivity also for acute pyelonephritis,
particularly if performed in the first 3–5 days after fever onset. The scan is tolerated
without any problem even in severely ill infants (Figs. 10.3 and 10.4).
Fig. 10.3 Male, 5 years. DMSA scintigraphy 8 months after acute pyelonephritis. Bilateral scar-
ring (left upper pole, right lower pole)
Fig. 10.4 Female, 6 years. Acute pyelonephritis. DMSA scintigraphy. Multiple hypoactive areas
confirming the diagnosis
Static renal scintigraphy represents probably the most sensitive technique

for identifying ectopic functioning kidney, and even very small kidneys are
visualized.
10.3.4.3 Cystoscintigraphy
Cystoscintigraphy is the procedure of choice in the follow-up of VUR. It has the
best sensitivity and a negligible radiation exposure. It is indicated for the first diag-
nosis of VUR in selected patients, when the morphological data offered by
Fig. 10.5 Female, 4 years. Vesicoureteral reflux. Direct cystoscintigraphy, filling phase. Persistent
bilateral reflux
radiographic cystogram are not relevant (most frequently in female patients with a
negative urological anamnesis, with particular regard for the voiding patterns). It is
cheaper than cystonography, which requires a well-trained operator and at least in
some cases sedation (Fig. 10.5).
Suggested Reading
Bell LE, Mattoo TK (2009) Update on childhood urinary tract infection and vesicoureteral reflux.
Semin Nephrol 29(4):349–359
Duong HP, Piepsz A, Collier F, Khelif K, Christophe C, Cassart M, Janssen F, Hall M, Ismaili K
(2013) Predicting the clinical outcome of antenatally detected unilateral pelviureteric junction
stenosis. Urology 82(3):691–696
Feld LG, Mattoo TK (2010) Urinary tract infections and vesicoureteral reflux in infants and chil-
dren. Pediatr Rev 31(11):451–463
Ferreiro C, Piepsz A, Nogarède C, Tondeur M, Hainaut M, Levy J (2013) Late renal sequelae in
intravenously treated complicated urinary tract infection. Eur J Pediatr 172(9):1243–1248
La Scola C, De Mutiis C, Hewitt IK, Puccio G, Toffolo A, Zucchetta P, Mencarelli F, Marsciani M,

Dall’Amico R, Montini G (2013) Different guidelines for imaging after first UTI in febrile
infants: yield, cost, and radiation. Pediatrics 131(3):e665–e671
Montini G, Zucchetta P, Tomasi L, Talenti E, Rigamonti W, Picco G, Ballan A, Zucchini A, Serra
L, Canella V, Gheno M, Venturoli A, Ranieri M, Caddia V, Carasi C, Dall’amico R, Hewitt I
(2009) Value of imaging studies after a first febrile urinary tract infection in young children:
data from Italian renal infection study 1. Pediatrics 123(2):e239–e246
Nogarède C, Tondeur M, Piepsz A (2010) Normalized residual activity and output efficiency in
case of early furosemide injection in children. Nucl Med Commun 31(5):355–358
Piepsz A (2011) Antenatal detection of pelviureteric junction stenosis: main controversies. Semin
Nucl Med 41(1):11–19
Piepsz A, Sixt R, Gordon I (2010) Performing renography in children with antenatally detected
pelvi-ureteric junction stenosis: errors, pitfalls, controversies. Q J Nucl Med Mol Imaging
54(4):350–362
Piepsz A, Nogarède C, Tondeur M (2011) Is normalized residual activity a good marker of renal
output efficiency? Nucl Med Commun 32(9):824–828
Polito C, Rambaldi PF, Signoriello G, Mansi L, La Manna A (2006) Permanent renal parenchymal
defects after febrile UTI are closely associated with vesicoureteric reflux. Pediatr Nephrol
21(4):521–526
Polito C, La Manna A, Rambaldi PF, Valentini N, Marte A, Lama G (2007) Long-term evolution
of renal damage associated with unilateral vesicoureteral reflux. J Urol 178(3 Pt
1):1043–1047
Saadeh SA, Mattoo TK (2011) Managing urinary tract infections. Pediatr Nephrol 26(11):1967–
1976. doi:10.1007/s00467-011-1801-5
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reporting on renal cortical scintigraphy in children: a large collaborative study. Nucl Med
Commun 30(4):258–262
Tondeur M, Nogarède C, Donoso G, Piepsz A (2013) Inter- and intra-observer reproducibility of
quantitative renographic parameters of differential function and renal drainage in children.
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Zucchetta P, Artifoni L, Rigamonti W, Cecchin D, Bui F, Murer L (2010) Molecular biology and
nuclear medicine in pediatric hydronephrosis. Q J Nucl Med Mol Imaging 54(4):363–371
The Problem of Cancer in Children
11
Marta Podda, Veronica Biassoni, Cristina Meazza,
Elisabetta Schiavello Serena Catania, and Maura Massimino
Contents
11.1 Introduction .................................................................................................................. 187
11.1.1 Incidence ....................................................................................................... 187
11.1.2 Etiopathogenesis ........................................................................................... 187
11.1.3 General Principles of Treatment ................................................................... 187
11.1.4 Peculiarities of Treatment for Neoplasms in Pediatric Age ......................... 188
11.2 Central Nervous System (CNS) Tumors ...................................................................... 189
11.2.1 Epidemiology and Etiology .......................................................................... 189
11.2.2 Clinical Presentation ..................................................................................... 190
11.2.3 Diagnostic Workup: Instrumental Diagnostics and Staging ......................... 191
11.2.4 Pathology ...................................................................................................... 192
11.2.5 Treatment and Follow-Up ............................................................................. 194
11.2.6 Gliomas ......................................................................................................... 197
11.2.7 Medulloblastoma (Cerebellar PNET) ........................................................... 198
11.2.8 PNETs: Pineoblastoma ................................................................................. 198
11.2.9 Ependymoma ................................................................................................ 198
11.2.10 Germ Cell Tumors (GCT)........................................................................... 198
11.2.11 Brainstem Tumors....................................................................................... 199
11.2.12 Atypical Teratoid/Rhabdoid Tumor (AT/RT) ............................................. 199
11.3 Lymphomas .................................................................................................................. 200
11.3.1 Epidemiology................................................................................................ 200
11.3.3 Diagnosis and Staging .................................................................................. 201
11.3.4 Pathology ...................................................................................................... 202
11.4 Soft Tissue Sarcomas: Rhabdomyosarcoma ................................................................ 204
11.4.3 Diagnostic Workup and Staging ................................................................... 205
11.4.4 Pathology ...................................................................................................... 205
M. Podda (*) • V. Biassoni • C. Meazza • E.S.S. Catania • M. Massimino

Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
e-mail: marta.podda@istitutotumori.mi.it

DOI 10.1007/978-3-319-21371-2_11
186 M. Podda et al.
11.5 Non-Rhabdomyosarcoma Sarcomas (“Non-Rhabdo”) ................................................ 207

11.5.3 Pathology ...................................................................................................... 207
11.6 Bone Sarcomas............................................................................................................. 208
11.6.1 Osteosarcoma................................................................................................ 209
11.6.2 Ewing Sarcoma ............................................................................................. 211
11.7 Neuroblastoma ............................................................................................................. 213
11.7.2 Biological–Molecular Characterization ........................................................ 214
11.7.4 Treatment ...................................................................................................... 216
11.8 Thyroid Cancer ............................................................................................................ 216
11.8.1 Differentiated Thyroid Carcinoma................................................................ 217
11.8.2 Medullary Thyroid Carcinoma ..................................................................... 219
11.9 Melanoma .................................................................................................................... 219
11.9.2 Clinical Presentation and Diagnosis ............................................................. 220
11.9.3 Therapy ......................................................................................................... 220
11.10 Wilms’ Tumor ............................................................................................................ 220
11.10.1 Epidemiology and Etiology ........................................................................ 220
11.10.2 Clinical Presentation ................................................................................... 221
11.10.3 Diagnostic Workup and Staging ................................................................. 221
11.10.4 Pathology .................................................................................................... 221
11.10.5 Treatment .................................................................................................... 222
11.11 Germ Cell Tumor (GCT) ........................................................................................... 222
11.11.4 Pathology .................................................................................................... 224
11.11.5 Treatment .................................................................................................... 224
11.12 Nasopharyngeal Carcinoma ....................................................................................... 224
11.12.1 Epidemiology.............................................................................................. 224
11.12.3 Diagnosis .................................................................................................... 225
11.12.4 Treatment and Prognosis ............................................................................ 226
11.13 Retinoblastoma (RB) ................................................................................................. 226
11.13.4 Pathology .................................................................................................... 227
11.13.5 Treatment .................................................................................................... 228
11.14 Langerhans Cell Histiocytosis (LCH) ........................................................................ 228
11.14.3 Diagnosis and Staging ................................................................................ 229
11.14.4 Pathology .................................................................................................... 230
11.14.5 Therapy ....................................................................................................... 230
11.15 Hepatoblastoma (HB) [58] ......................................................................................... 230
11.15.4 Pathology .................................................................................................... 232
11.15.5 Treatment .................................................................................................... 232
References ................................................................................................................................ 232
11 The Problem of Cancer in Children 187
11.1 Introduction
11.1.1 Incidence
Forty percent of pediatric neoplasms develop by 4 years of age, with a slight preva-
lence in males, the male–female ratio being 1:1.2. In industrialized countries, the can-
cer incidence in children is approximately 130–140 new cases per million children a
year, meaning that in Italy, for instance, there are about 1350 new pediatric cases of
cancer every year. Taking all the malignant histotypes into account, recent data indi-
cate that 70 % of patients are now still alive 5 years after their diagnosis [88].
11.1.2 Etiopathogenesis
While mutagenic environmental factors are the main culprits implicated in adult
tumors, in pediatric neoplasms, the factors involved are more likely to be genetic.
Genetic Factors
• Chromosomal anomalies
• Monogenic anomalies (mutation of one or both alleles)
• Polygenic or multifactorial anomalies (several genes interact, in association with
environmental factor, in triggering diseases in which no particular gene or factor
has a dominant role)
Familial clusters of certain neoplasm are suggestive of a genetic predisposition.
Environmental Factors
• Exposure to ionizing radiation
• Exposure to chemical agents (e.g., diethylstilbestrol taken by the mother during
pregnancy is associated with a higher risk of vaginal and cervical adenocarci-
noma in girls)
• Antineoplastic chemotherapy (there is a relationship between the administration
of alkylating agents, especially when combined with radiotherapy, and the sub-
sequent onset of second neoplasms)
• Viral agents (e.g., EBV infection and the onset of Burkitt lymphoma, especially
in African children, and undifferentiated rhinopharyngeal carcinoma or HBV
infection and hepatocarcinoma)
• Parents’ working environments (e.g., exposure to lead and hydrocarbon), duration of
breastfeeding, and exposure to electromagnetic fields are currently under study as
factors potentially influencing a child’s predisposition to malignant neoplasms [88].
11.1.3 General Principles of Treatment
Surgery A diagnostic biopsy should always be considered if it is impossible to

ensure a radical resection or if a lymphoma for which surgery is not curative is
suspected. The basic goal of surgery in oncology is to remove the tumor together
188 M. Podda et al.
with a clear margin of healthy tissue if at all possible in order to ensure surgical
radicality.
Chemotherapy This may be adjuvant (administered after the primary tumor has
been resected in cases of localized disease) or neoadjuvant (administered in the
presence of an inoperable primary tumor, or when “d’emblée” surgery is not indi-
cated, or in the event of metastatic disease). Tumor cells acquire various mecha-
nisms that confer resistance to chemotherapeutic agents, so combinations of drugs
are often used, rather than sequential treatments with single drugs, in order to target
several subpopulations of tumor cells at once.
The testicle and the central nervous system are anatomical regions that are so-
called tumor “sanctuaries” because they are difficult for chemotherapeutic agents
administered intravenously, intramuscularly, or orally to access.
In particular, the blood–brain barrier represents an obstacle to the drugs’ penetra-
tion inside the CNS, and that is why it may be useful in selected cases to administer
the chemotherapy intrathecally.
Radiotherapy Conventional radiotherapy uses photons, but electrons, protons,

and neutrons may be used too. Not all tumors are radiosensitive, and radiotherapy
may not always be warranted even if they are.
11.1.4 Peculiarities of Treatment for Neoplasms in Pediatric Age
Among the particular features of the treatments used in pediatric oncology, there is
primarily the acknowledged need for a multimodal approach and a multidisciplinary
treatment. This means that several specialists (radiologists, pediatric oncological
surgeons, pathologists, radiotherapists, nurses, physiatrists, physiotherapists, neu-
rologists, medical psychologists, social workers) should work together with the
pediatric oncologist, who takes responsibility for the diagnostic workup, the appro-
priate choice of treatment, its implementation, and the patient’s follow-up.
Secondly, as a part of the diagnostic–therapeutic procedure for each specific
pediatric neoplasm, it is always essential to consider the possible iatrogenic
sequelae, making every attempt to cure the disease while containing the damage that
we now know can be caused by its treatment. Assessing sequelae consequently
becomes an integral part of every pediatric patient’s follow-up, together with the
control of any recurrent disease.
Lastly, it is important to bear in mind that patients cured of a pediatric neoplasm
have a cumulative 12 % probability (20 times higher than for the general popula-
tion) of developing other tumors within 20 years of their first neoplasm’s diagnosis.
This higher risk derives from the fact that these individuals will presumably have a
hereditary predisposition (hence their pediatric neoplasm) combining with the
effects of therapies for their primary tumor, and oncogenic environmental factors
are likely to find in them a terrain genetically more susceptible to the development
of new neoplastic diseases [10].
11.2 Central Nervous System (CNS) Tumors
11.2.1 Epidemiology and Etiology
CNS neoplasms are the most common solid tumors in childhood, accounting for one
in four tumors developing in pediatric age. With an incidence of 2.4 new cases per
100,000 a year, they are the first cause of tumor-related death in this age group [31].
A higher risk of developing primary CNS tumors has been associated with a his-
tory of radiation to the CNS and with certain genetic syndromes (neurofibromatosis
types I and II, Li–Fraumeni syndrome, bilateral retinoblastoma, tuberous sclerosis,
von Hippel–Lindau disease, Gorlin syndrome, Cowden syndrome, Turcot syn-
drome, Pierpont syndrome, and ataxia–telangiectasia). These conditions are
involved in 5 % of pediatric brain tumors (BTs). Physicians managing patients with
these syndromes should bear this association in mind and watch for any signs or
symptoms suggestive of CNS tumors [55, 104]. Relatively consistent evidence is
accumulating, from larger studies and meta-analyses, of positive associations
between pediatric CNS tumors and parents’ advanced age, birth defects, fetal
growth markers, computed tomography (CT) scans, nitroso compounds in the
mother’s diet, and exposure to residential pesticides [53].
Unlike the situation seen in adults, who usually develop high-grade astrocytomas
(WHO grades III and IV), the histotypes most frequent in childhood are low-grade glio-
mas and embryonic tumors (PNET and medulloblastoma), which account, respectively,
for 50 % and 20 % of CNS tumors in children under 15 years of age [47] (Fig. 11.1).
Fig. 11.1 Pediatric CNS tumors according to histology

190 M. Podda et al.
11.2.2 Clinical Presentation
11.2.2.1 Initial Signs and Symptoms

Initial signs and symptoms depend on the primary site of the neoplasm in relation to
the cerebral structures and on the child’s age [114].
11.2.2.2 Signs of Endocranial Hypertension

Signs of endocranial hypertension can develop quite late, partly because of the
skull’s plasticity (which is all the greater the younger the patient involved) and
partly because the brain is still malleable in childhood and may be compressed
without any neurological changes becoming apparent.
11.2.2.3 Ocular Fundus Anomalies

In the newborn, the fundus may be normal despite endocranial hypertension,
whereas older children more frequently show signs of papillary edema and hem-
orrhage, sometimes associated with a decline in visual acuity and even amauro-
sis. It is worth bearing in mind that papillary edema is always a sign of
endocranial hypertension, but the absence of the former does not rule out the
latter.
11.2.2.4 Signs of Brain Herniation

If endocranial hypertension goes undiagnosed, there may be signs of brain
herniation:
• Uncal (tentorial) herniation: due to craniocaudal pressure sufficient to make the

deepest and most medial part of the temporal lobe (uncus) herniate through the
tentorial notch, compressing the brainstem structures, interfering with the state
of vigilance, and causing motor pathway suffering with hemiparesis–hemiplegia
of the contralateral side and third cranial nerve impairment
• Cerebellar (subtentorial) herniation: engagement of the cerebellar tonsils in the
occipital foramen, reaching as far as the bulb and spinal canal and causing an
altered state of consciousness, bradypnea and bradycardia, episodes of decere-
brate and opisthotonic posturing, and stiffness.
11.2.2.5 Focal Signs

Supratentorial tumors may be disclosed by lateral impairment syndromes, partial
epileptic seizures, psychic changes (mood disorders, abulia, poor academic perfor-
mance), and eyesight impairments, depending on the suprachiasmatic sites
involved. In tumors of the posterior fossa, there may be evidence of cerebellar
syndrome and/or progressive hemiplegia associated with eye movement paralysis.
There may also be concomitant neuroendocrine disorders, such as a late or early
onset of puberty, delayed height or weight gain, and trophic alterations in the case
of diencephalic neoplasms (diencephalic syndrome becomes manifest with failure
to thrive). Optic nerve gliomas can become apparent from a decline in visual acuity
and proptosis.
11.2.3 Diagnostic Workup: Instrumental Diagnostics and Staging
When clinical signs and symptoms are suggestive of CNS tumors, it becomes man-
datory to conduct specific instrumental investigations because no blood chemistry
tests are capable of orienting toward a diagnosis of neoplastic disease [82].
1. Computerized axial tomography (CT): This method is useful in emergency con-

ditions to assess hydrocephalus, bleeding, and liquor or blood collections or to
identify calcified lesions.
2. Nuclear magnetic resonance imaging (NMRI): This is the standard method for
diagnosing patients with a suspected CNS neoplasm and for assessing response
to treatment. MRI provides additional anatomical details concerning the tumor’s
topography, extent, and solid and liquid components. Nuclear MRI enables
images to be constructed on sagittal, coronal, and axial planes that are particu-
larly useful for assessing the anatomy of the posterior fossa and brainstem. T1
sequences provide a good degree of anatomical detail, while differences between
normal and pathological tissues emerge on T2 images. Imaging with fluid attenu-
ation inversion recovery (FLAIR) and T2 sequences reveal areas where the
blood–brain barrier is disrupted and evidence of neoplastic infiltration and
edema. NMRI can document areas of treatment-related leukomalacia so it has an
indispensable role in the follow-up of iatrogenic sequelae too.
3. Positron emission tomography (PET): This method may be useful for distin-
guishing tumor recurrence from radiation-induced necrosis, especially in tumors
with a high level of metabolic activity. Malignant tumors tend to be hypermeta-
bolic compared with surrounding tissues, while necrotic tissue is hypometabolic.
This distinction is scarcely applicable to childhood brain tumors, however. PET
can also be used to highlight functionally important and therefore unresectable
brain areas in children. A chapter in this book is dedicated to the characteristics
and diagnostic value of PET.
The purpose of staging is to establish the extent of the tumor, its dimensions, and
any subarachnoid dissemination. Extracerebral and lymph node metastases are
extremely rare.
Staging relies on the following methods:
1. Postoperative NMRI of the brain and spinal cord, with and without contrast
medium: The spinal cord should preferably be assessed before surgery to avoid
false-positive results. Imaging within 48 h after surgery can provide a reliable
idea of residual tumor volume (which may have prognostic implications and
may be used to decide for the therapeutic strategy).
2. Diagnostic lumbar puncture: This test is indispensable for identifying any
liquoral dissemination of the disease (liquor cytology) or liquor circulation dys-
functions (biochemical tests). It can also be used to test for specific markers
(such as αFP and βHCG, which are diagnostic of germ cell tumors).
No unified staging system currently exists for CNS tumors.

192 M. Podda et al.
11.2.4 Pathology
The currently used histological classification was developed by the World Health
Organization (WHO) and was last revised in 2007 [63]. In recent years, molecular
biology and molecular cytogenetics have gained importance for identifying tumor-
specific genetic changes and molecular markers of prognostic and/or therapeutic
interest, influencing the histopathological classification of these neoplasms. In the
biological setting, the most important recent discovery concerns the isolation, in
pediatric as well as adult brain tumors, of variable proportions of genetically modi-
fied cells (tumor stem cells) with the distinctive characteristics of specific neural
precursors existing at various brain sites, i.e., the expression of specific immuno-
phenotypic markers and their expression profiles relating to signal pathways
involved in neural development, a capacity for self-renewal, and a capacity for gen-
erating a variety of tumor cells. The main histopathological and molecular charac-
teristics of the tumors most often encountered in pediatric age – i.e., gliomas, neural
neoplasms, embryonic neoplasms, germ cell tumors, choroid plexus tumors, and
meningiomas – are listed below.
11.2.4.1 Gliomas
Gliomas derive from glial cells and include astrocytomas, oligodendrogliomas,
ependymomas, and choroid plexus tumors.
Pilocytic astrocytoma (WHO grade I) originates mainly in the cerebellum but
also in the third ventricle, the optic and chiasmatic pathways, the basal ganglia,
and the spinal cord. B-RAF gene mutations are quite common, being found in
20 % of these tumors in pediatric age. Diffuse astrocytoma (WHO grade II) usu-
ally involves the brainstem and spinal cord. Anaplastic astrocytoma (WHO grade
III) and glioblastoma (WHO grade IV) are morphologically similar to their coun-
terpart in adults, but in children, the p53 mutation is more common, while EGFR,
PTEN, p14, and p16 gene mutations are rare. Glioblastoma multiforme (grade IV)
is an astrocytic variant in which the anaplastic features dominate the picture.
Malignant gliomas account for approximately 10–15 % of brain tumors in
children.
Ependymomas (10 % of pediatric brain tumors) derive from the ependyma and
develop in the vicinity of the ventricular structures, including the spinal canal. In
children and young adults, they tend to occur at intracranial sites, with a predilec-
tion for the fourth ventricle. In adolescents and older adults, spinal localizations are
more common [37].
Most ependymomas are classified as WHO grade II. Less frequently, they may
show histological signs of anaplasia with numerous mitosis, vascular proliferation
and necrosis, and a more aggressive clinical behavior (anaplastic ependymoma,
WHO grade III).
NF2 gene mutations are found in cases of spinal ependymoma, but not in patients
with intracranial tumors. Gain of 1q has been associated with a worse prognosis.
Gene expression analyses have revealed the activation of various pathways involved
in neural development and NOTCH in particular [76, 95].
Choroid plexus tumors derive from the specialized choroid plexus cells respon-
sible for producing the cerebrospinal fluid. In pediatric age, they occur mainly
within the lateral ventricles.
11.2.4.2 Neural and Mixed Glioneuronal Neoplasms

Neural and mixed glioneuronal neoplasms are rare and generally have a favorable
course. They tend to occur mainly in adolescents and young adults. The sites most
often affected are the temporal lobe, the floor of the third ventricle, and the hypo-
thalamus. Histologically, these neoplasms consist of mature neural cells (gangliocy-
toma) sometimes associated with a glial component (ganglioglioma). This group
also includes even rarer forms, such as neurocytoma, dysembryoplastic neuroepi-
thelial tumor (DNET), and glioneuronal papillary tumor. These lesions often cause
long-term drug-resistant epilepsy. Desmoplastic infantile astrocytoma/ganglioglioma
(WHO grade I) is a separate entity.
11.2.4.3 Embryonal Neoplasms

Embryonal neoplasms derive from primitive embryonal cells. They typically
develop early in childhood and are highly malignant, and consequently all are clas-
sified as WHO grade IV. Embryonal neoplasms include medulloblastoma, primitive
neuroectodermal tumors (PNETs), and atypical teratoid/rhabdoid tumor (AT/RT).
Medulloblastomas account for 10–20 % of BTs and 40 % of tumors of the pos-
terior fossa, often arising from the cerebellar vermis or fourth ventricle. Various
subtypes (classic, nodular/desmoplastic, large cell/anaplastic) have been identified
that correlate with prognosis and are consequently now used to orient the choice of
treatment. Other molecular subtypes and genetic patterns of prognostic significance
have emerged from recent studies, i.e., ERB-B2, TRKC, PDGFRA, MYCC, and
MYCN expression of β-catenin, and will be considered in upcoming clinical trials.
Seeding may occur into the subarachnoid space, CSF, or supratentorial sites and
rarely into the bone marrow, bones, and liver [68, 97].
Non-cerebellar PNETs account for 2–3 % of pediatric CNS tumors. They are
generally localized in one of the hemispheres and are locally extensive, often with
leptomeningeal dissemination.
11.2.4.4 Germ Cell Tumors

Germ cell tumors make up 3.5 % of pediatric brain neoplasms, with a higher inci-
dence in males and a mean age of onset around 12 years. The sites most often
affected are located along the midline, in the pineal gland, the suprasellar region,
and the third ventricle [79]. At CNS level, a distinction is drawn between secreting
and nonsecreting germinomas, depending on the presence of pathological levels of
αFP and/or βHCG in the serum and/or liquor.
11.2.4.5 Meningiomas
Meningiomas develop mainly in adult age, representing almost 20 % of all intracra-
nial primary neoplasms. They may occasionally develop in pediatric age too. The
most common molecular change involves the loss of chromosome 22 with NF2
194 M. Podda et al.
gene deletion or mutations. There is a high incidence of meningioma, often involv-

ing multiple sites, in patients with neurofibromatosis type II, in which the gene is
mutated at germinal level.
11.2.5 Treatment and Follow-Up
This always includes primary surgery, whenever it is technically feasible.

Complementary treatment with chemotherapy and/or radiotherapy may be pro-
vided, depending on the outcome of surgery and on the histotype involved. In all
cases, a patient’s treatment should be planned jointly by a team including the neu-
rosurgeon, pediatric oncologist, pathologist, radiotherapist, and neuroradiologist.
11.2.5.1 Surgery
Indications Surgery is indicated in the majority of cases, and children should ide-
ally be operated only by surgeons specializing in pediatric diseases.
Treatment for Hydrocephalus The indication for surgery must take into account
any hydrocephalus, which should always be treated before any attempt at surgery on
the tumor mass. Hydrocephalus can be treated by means of shunts (internal or external
ventricular shunts, depending on the duration of the drainage) or endoscopically [45].
11.2.5.2 Radiotherapy
Irradiation has a role in preventing local recurrences and tumor spread. When an adju-
vant chemotherapy is used before radiotherapy, it is important to bear in mind that
some chemotherapeutic agents have a toxicity of their own that compounds the
expected toxicity of the radiation treatment (for instance, methotrexate is neurotoxic
and cisplatin can sensitize the inner ear to radiation-induced damage). Depending on
the tumor’s histology, the volume to irradiate may coincide with the tumor alone
(administering 50–55 Gy) or the tumor plus the neural axis (administering from 23 to
36 Gy on a level with the brain and spinal cord). Radiotherapy is administered in daily
fractions of 1.6–1.8 Gy for 5 days a week. Hyperfractionation (administering more
than one fraction a day in reduced doses, e.g., 1.1–1.3 Gy every 6–8 h) is an unconven-
tional method used in controlled clinical trials with a view of increasing the biologi-
cally effective dose of radiation while reducing the side effects on the healthy tissues.
All candidates for radiotherapy to the CNS should be treated after formulating a
treatment plan with the aid of software capable of generating 3D images from combina-
tions of MRI and CT findings. The term “conformal radiotherapy” refers to any radio-
therapeutic method that enables the distribution of the therapeutic dose to be shaped to
fit the target tumor volume, reducing the level of radiation absorbed by the surrounding
healthy tissues. This can be achieved using various methods, such as fixed-beam 3D
conformal radiotherapy, multiple-arc stereotactic radiotherapy, intensity-modulated
radiation therapy (IMRT), tomotherapy, and so on. Another approach exploits the pecu-
liar physical characteristics of hadrons, and of proton beams in particular, to make the
radiation even more conformable and thus better safeguard adjacent healthy tissues [72].
11.2.5.3 Chemotherapy
The presence of the blood–brain barrier makes chemotherapy less effective in BTs
than in solid tumors occurring at other sites. The drugs most often used to treat
pediatric brain neoplasms are the nitrosoureas, vincristine, procarbazine, platinum
derivatives, epipodophyllotoxins, high-dose methotrexate, and other antimetabo-
lites. Among the drugs used most recently, it is worth mentioning temozolomide,
which achieves a good bioavailability after oral administration and causes minimal
myelosuppression.
Intrathecal and intraventricular chemotherapy relies mainly on methotrexate and
should be omitted after radiotherapy to the neural axis to avoid cumulative toxicity
phenomena. Some protocols recommend chemotherapy before radiotherapy, as early
as possible after surgery, based on the assumption that postoperative anatomical
changes may facilitate the drugs’ passage through the blood–brain barrier. One way
to overcome the obstacle represented by the blood–brain barrier consists in deposit-
ing the drug directly within the tumor bed. In selected cases, and subject to the exper-
tise available at the center involved, high-dose chemotherapy followed by autologous
marrow or peripheral stem cell transplantation may be used postoperatively for neo-
plasms with an unfavorable prognosis relating to their histotype or stage or to the
patient’s age. This treatment suffers from a high morbidity rate and high costs, how-
ever, and only centers specializing in pediatric oncology and equipped to perform
this type of treatment can adopt such complex therapeutic protocols.
11.2.5.4 Biological Treatment

The characterization of new signal transduction pathways implicated in the genesis
and progression of CNS tumors has given rise to a number of new drugs and thera-
peutic approaches for neoplasms that fail to respond to conventional treatments.
Such novel agents include specific inhibitors (small molecules), monoclonal anti-
bodies (moAb), and angiogenesis inhibitors. The majority of these new drugs need
further clinical testing (some of which is currently under way) to establish their
optimal dosage, alone or in combination, and to ascertain their additive potential or
possible synergic effects.
Using vaccines obtained by charging dendritic cells with glioblastoma proteins
or tumor lysates, various phase 1 studies have demonstrated that vaccination is a
safe procedure and capable of contributing to a significant improvement in overall
survival. Research in pediatric neuro-oncology has tested the feasibility of this pro-
cedure in children too, particularly in cases in which recurrence have been macro-
scopically completely resected. It remains to be seen whether such cell therapy
approaches can be included in multicenter protocols, given the assurance of good
clinical practice that such a refined cell manipulation demands.
11.2.5.5 Salvage Therapy

It is not always advisable to attempt further therapies if a brain tumor evolves
despite primary treatment. A second surgical procedure should always be consid-
ered, albeit with the limitations intrinsic in brain anatomy and the greater risks asso-
ciated with resurgery in tissues that have become abnormally revascularized after
radiotherapy – especially in neoplasms of low-grade malignancy and
196 M. Podda et al.
ependymomas. Where feasible, radiotherapy could be repeated, in doses depending

on the site of the recurrence and the dosage already administered. Various other
drugs, from the classic chemotherapeutic agents to the biological options, alone or
in association, have also been used as second-line treatments.
Flowchart 11.1 shows the general diagnostic workup for CNS neoplasms. Then
the last part of this chapter goes into further detail concerning the diagnosis and
treatment of the main histotypes.
Oncological Follow-Up This involves regular clinical and radiological assess-

ments, their frequency depending on the type of tumor, the treatment administered,
and the time elapsing since its completion [81]. Children with severe neurological
impairments immediately after surgery are unlikely to recover completely, and per-
sistently high intracranial pressures can lead to atrophy of the optic pathways and
visual impairments. Children presenting with supratentorial disease may have con-
vulsions even after completing their treatment and consequently require long-term
antiepileptic medication.
In addition to follow-up visits, objective neurological assessments and NMRI,
neuropsychological and endocrinological assessments should be an integral part of
the follow-up for children treated for CNS neoplasms. Nowadays, more than one in
Neuorendocrine changes
Signs of endocranial Focal neuological signs

hypertensions (headache, (ataxia, cranial nerve
vomiting, papillary edema) Suspected brain impairments, motor
tumor deficiencies, epilepsy)
CNS imaging studies,

Brain MRI, preferably with spinal MRI
CT in cases where MRI is unavailable
No evidence of neoplastic disease Brain tumor
In cases of
hydrocephalus
Clinical monitoring Further assessments consider urgent
depending on site of liquor shunting
lesion and start
dexamethasone
Pinal,
Supratentorial Subtentorial
suprasellar or
lesions lesions
optic pathway
lesions
Flowchart 11.1 Diagnostic flow-chart of brain tumors

two children who develop brain tumors have a chance of being cured and reaching
adulthood, but the price to pay is often high in terms of the sequelae, which become
manifest in neurocognitive, endocrinological–metabolic, and somatic growth
impairments. Efforts focusing on the prevention, rehabilitation, and correction of
these deficits are consequently an integral part of the treatment plan for children
with brain tumors.
11.2.6 Gliomas
11.2.6.1 Low-Grade Histotypes

Maximally safe resection (generally achievable for hemispheric or cerebellar loca-
tions) has significant prognostic implications in these tumors. They are typically
well circumscribed but quite frequently include a subtle component that may be
hard to differentiate from normal surrounding brain tissue. Real-time imaging with
navigational capabilities may be helpful during surgery to maximize resection con-
trol. Chemotherapy is not generally necessary, but several clinical trials have dem-
onstrated that it has a role in stabilizing or shrinking low-grade gliomas, so it is used
in progressive or unresectable tumors. The most widely used chemotherapy regi-
mens are carboplatin and vincristine, cisplatin and etoposide, and vinblastine [80].
Radiotherapy is not a first choice (due to its long-term side effects in populations
with an excellent prognosis). In fact, radiation-induced tumors are a concern in
patients with low-grade glioma associated with genetic syndromes, such as phaco-
matosis. These conditions carry a very good prognosis, with 5-year overall survival
rates > 90 % after complete (and often curative) surgical resection. The follow-up
should be more frequent in the event of residual disease, with or without ophthalmo-
logical assessment for optic pathway gliomas, and/or endocrinological assessment,
depending on the site of the lesion.
11.2.6.2 High-Grade Histotypes

These neoplasms have an infiltrative growth pattern and a rapid growth rate and
often recur after treatment. At present, the strongest prognostic indicator is the
extent of resection, but radical surgery is often not feasible due to the infiltrative
pattern and the tumor’s location, frequently involving the thalamus and pons. Biopsy
is advisable in cases of diffuse intrinsic pontine glioma (DIPG) or gliomatosis cere-
bri to ascertain the disease’s biological characteristics and orient the choice and
targeting of treatments, especially in clinical trials. High-dose focal radiation after
maximal surgery is the best treatment strategy. There is currently no officially
acknowledged standard chemotherapy, but, based on experience in adults, adding
oral temozolomide to radiotherapy and for maintenance has long been considered as
such [109]. Myeloablative chemotherapy is not standard but is used for first-
diagnosed and relapsing tumors, with variable results [65]. Target therapies (gefi-
tinib, erlotinib, imatinib, nimotuzumab) are currently being tested in combination
with conventional therapies [64]. The median overall survival for patients with
high-grade tumors is around 12–24 months.
198 M. Podda et al.
11.2.7 Medulloblastoma (Cerebellar PNET)
Maximal safe resection is the mainstay of treatment. Postoperative staging enables

patients to be classified as standard risk (residual disease ≤1.5 cm2, no metastases)
or high risk (residual disease >1.5 cm2 and/or metastases). Chemo- and radiotherapy
(RT) are both mandatory after surgery. The aim of RT is to control residual disease
and avoid subarachnoid dissemination. In cases of localized disease, the standard
treatment includes craniospinal irradiation (CSI; 23.4 Gy) plus a boost on the tumor
site (30.6 Gy) and chemotherapy using various schedules (vincristine, cisplatin, eto-
poside, carboplatin, cyclophosphamide, and lomustine). For metastatic disease, the
strategy currently used at our institute includes pre-radiation intensive chemother-
apy and hyperfractionated accelerated radiotherapy (HART), with or without subse-
quent consolidation with myeloablative chemotherapy. With this treatment
approach, the event-free survival rate (EFS) at 5 years rises from 50 to 70 % [43].
11.2.8 PNETs: Pineoblastoma
After maximal safe resection, adjuvant therapy consists of radiation to the tumor
bed (40–60 Gy) and, in selected cases, to the neuraxis (30–35 Gy), associated with
chemotherapy (nitrosoureas, procarbazine, cyclophosphamide, vincristine, cispla-
tin, and carboplatin). This approach has recently been intensified with the addition
of myeloablative schedules in order to reduce the radiation doses/fields and improve
the patient’s prognosis [34]. Only 35 % of patients are alive at 5 years.
11.2.9 Ependymoma
Gross-total safe resection has a primary prognostic influence: The 5-year survival
rate is about 70 % for near complete resections as opposed to about 40 % for subto-
tal resections. Second-look surgery is justified when postoperative imaging suggests
residual disease or during treatment. Radiotherapy is essential, even after complete
resection, with total doses to the tumor bed of 59.4 Gy; the role of a boost to any
residual disease is the object of ongoing international studies [66]. Adjuvant chemo-
therapy can be recommended, within controlled clinical trials, in cases of residual
disease or unfavorable histology to shrink the residual tumor and enable total resec-
tion at second-look surgery [69]. Late recurrences can occur, for which complete
surgery is always the goal, possibly followed by re-irradiation.
11.2.10 Germ Cell Tumors (GCT)
There are two subtypes of this disease: pure germinomas (accounting for two in
every three GCTs) and “nongerminomatous germ cell tumors” (NGGCT), which
can be associated with pathological αFP/βhCG findings in the serum or CSF. Surgical
removal is not recommended because of these neoplasms’ high chemo- and/or

radiosensitivity, but surgery is important in establishing the histological diagnosis
as well as for the treatment of hydrocephalus, and it is essential for diagnostic pur-
poses if αFP/βhCG levels in the serum or CSF are not pathological. Debulking
procedures may be recommended in NGGCT as they are often chemotherapy resis-
tant. To contain or avoid exposure to radiation, platinum-based chemotherapeutic
regimens are used to good effect. Radiotherapy fields should include whole ven-
tricular systems. RT alone on the whole CNS can be curative in cases of metastatic
disease. Germinomas have long-term survival rates >90 %, while NGGCTs carry a
worse prognosis, with a 5-year overall survival (OS) rate of 60–70 %, and treatment
for the latter must include both platinum-based regimens and radiation therapy.
Endocrinological sequelae should be carefully monitored during the follow-up and
also the markers found pathological at diagnosis [56].
11.2.11 Brainstem Tumors
These are usually astrocytomas; they account for 10–15 % of all pediatric intracra-
nial tumors and 20 % of posterior fossa tumors. They have different degrees of
malignancy and infiltrate the brainstem extensively. Symptoms are usually rapidly
progressive.
Among the three patterns seen in brainstem lesions, diffuse infiltrating pontine
glioma (DIPG) is the most common. A single cycle lasting 5–7 weeks of radio-
therapy (54 Gy) is generally recommended, but the median OS is less than 1 year.
Neither standard nor high-dose adjuvant chemotherapy has proved capable of
modifying the prognosis. Recent molecular studies have shed light on the genetic
profiles of DIPG, showing that EGFR, PDGFR, and H3F3D are involved in differ-
ent subsets of these gliomas [112, 115]. These findings may have great promise
when applied to new therapeutic strategies in the future.
11.2.12 Atypical Teratoid/Rhabdoid Tumor (AT/RT)
This is an aggressive neoplasm characteristic of infancy with a dismal prognosis

[21]. It is usually located in the posterior fossa and cerebral hemispheres. It has been
recognized as a separate entity from PNET/medulloblastoma due to the presence of
rhabdoid cells and components of malignant mesenchymal and epithelial cells. It is
cytogenetically characterized by monosomy of 22q11 (and the hSNF/INI1 gene is
involved).
A sizable proportion of cases carries de novo SMARCB1 constitutional muta-
tions in the setting of the “rhabdoid tumor predisposition syndrome,” and the out-
come is worst in infants with syndromic AT/RT. Multiple therapeutic approaches
have been attempted over the last two decades to improve survival, without success.
There is no accepted standard chemotherapy, but intensive alkylator-based chemo-
therapy, high-dose methotrexate, and high-dose regimens with stem cell rescue may
200 M. Podda et al.
Table 11.1 Treatment and prognosis of most frequent pediatric brain tumors
Tumor Therapy Overall survival % at 5 years
Gliomas
Cerebellar astrocytoma
Low-grade, complete surgery S 90
High-grade, partial surgery S, LR ± C 15
Diffuse pontine glioma LR ± S (±C) <10
Supratentorial astrocytoma
Low-grade:
Complete surgery S 80
Partial surgery S ± LR (±C) 70
Ηigh-grade S, LR, C 35
Glioblastoma S, LR, C 10
Medulloblastoma
Age ≥ 3 years S, LR, CSI, C 80
Age < 3 years S, C, ± LR/CSI 70
Ependymoma
Complete surgery S, LR 70
Partial surgery S, LR ± C 40
Pineal region
Germ cell tumors (all) S, LR ± CSI ± C 70
Pineoblastoma S, CSI, LR ± C 40
Other non-cerebellar PNETs S, CSI, LR ± C 40
Choroid plexus carcinoma S, LR ± C 40
All tumors 60
S surgery, LR local radiotherapy, CSI craniospinal irradiation, C chemotherapy
prove more effective. Focal radiation is a crucial treatment. Overall survival is less
than 30 % at 12 months, and progression-free survival (PFS) at 1 year is less than
20 %.
Table 11.1 shows the survival rates for the various types of CNS neoplasm using
the currently recommended treatments [10].
11.3 Lymphomas
11.3.1 Epidemiology
Non-Hodgkin Lymphoma Non-Hodgkin lymphoma (NHL) accounts for approxi-

mately 10–15 % of all malignant neoplasms of pediatric age, and their incidence
rises constantly with age. The etiology of NHL remains largely unknown, with the
exception of significant associations with Epstein–Barr viral infection and African
Burkitt lymphoma and a predisposition associated with certain congenital syn-
dromes related to immunodeficiency. Overall, in Europe and the United States,
50–60 % of cases of pediatric NHL are Burkitt/Burkitt-like and mature large B-cell
NHL, while 30 % are lymphoblastic lymphomas (mainly intermediate or late pre-
cursor T-cell and, less frequently, B-cell neoplasms), and 10–15 % are anaplastic
large cell lymphomas. Other variants that are common in adults are rare in children
and adolescents.
Hodgkin Lymphoma Hodgkin lymphoma (HL) accounts for approximately 6 %

of pediatric neoplasms. It shows a predilection for males, especially in younger age,
and a bimodal distribution in its incidence, with a first peak between 15 and 30 years
of age and a second beyond the age of 50. For HL too, there is no clear etiology,
with the exception of a frequent association with high anti-EBV antibody levels and
with EBV genomes in the Hodgkin and Reed–Sternberg cells, particularly in devel-
oping countries.
The clinical presentation depends on the histotype, but it always correlates with the
site affected by the disease. Often it is associated with systemic symptoms such as
fever, weight loss, swallowing, pruritus, and asthenia.
11.3.3 Diagnosis and Staging
Staging Cytohistology is a fundamental element in the diagnosis of lymphoma.

When adenopathies are present, lymph node biopsy and lymphadenectomy are
mandatory (whereas fine needle biopsies should be avoided because of their limited
diagnostic value). If there is evidence of ascitic fluid or pleural effusion, cytologic
examination may substitute histology for diagnosis. In addition to the standard
radiological investigations (CT/MRI) of the chest and abdomen and of the affected
region, staging includes bilateral bone marrow evaluation and diagnostic lumbar
puncture for NHL, while only bone marrow biopsy is indicated for HL. Some
authors have reported that FDG-PET can accurately predict the outcome of bone
marrow biopsy for staging purposes, suggesting that bone marrow biopsy may be
omitted in patients with PET findings of bone marrow involvement [18]. The stag-
ing of pediatric NHL is that developed by Dr. Murphy at the St. Jude Children’s
Research Hospital in Memphis, while HL is currently staged using the Ann Arbor
protocol (1971), as revised in 1989.
The role of PET Over the last decade, PET has gradually replaced gallium scan as
the preferred functional imaging modality for lymphoma staging. In adult lympho-
mas, several studies have shown the superiority of PET/CT over classic radiological
investigations for the initial workup and for assessing remission. The ability of PET/
CT imaging to integrate the tumor’s functional and anatomical characteristics has
prompted its use for staging and monitoring pediatric patients with lymphoma
202 M. Podda et al.
because it is both accurate and cost-effective. Emerging studies also tend to support
the prognostic value of a persistent PET/CT positivity after 2 chemotherapy courses,
which could warrant an early assessment of the refractory disease. Very limited data
are available on the specificity and sensitivity of this method in childhood NHL
(apart from primary mediastinal large B-cell lymphoma, which is similar in children
and adults), but some studies report high sensitivity and specificity rates for FDG-
PET in assessing treatment response. The ability of FDG-PET to image hypermeta-
bolic tumors could make it a reliable method for detecting all sites of disease at
diagnosis. Information from FDG-PET may influence treatment planning by
prompting an upstaging or downstaging of the disease. It may therefore spare down-
staged patients the long-term side effects of intense chemotherapy and enable more
effective treatment to be offered for upstaged lymphomas. In contemporary, risk-
adapted chemoradiotherapy regimens, response to therapy is frequently a criterion
for tailoring therapy. Identifying the metabolic tumor activity through PET serves as
a surrogate measure of tumor response and often makes it unnecessary to document
disease status with invasive procedures.
In the pediatric population, PET imaging has some peculiarities: To obtain an opti-
mal scan, the patient must lie quietly to minimize FDG uptake related to muscle move-
ments and not to tumor activity and also to minimize the need of a sedation. Even in
ideal conditions, the avidity of FDG for certain structures such as brown fat or the
cervical musculature may hinder the interpretation of signs of nodal involvement by
lymphoma. An abnormal FDG avidity may be seen in patients treated with granulocyte
growth factors (involving a transient, intense FDG avidity in the spine, pelvis, and
spleen) or in images of patients recovering from an infectious/inflammatory process.
During the follow-up, PET can be useful only when standard radiological methods
pose a doubt of relapse. Clinicians should be aware that – in certain conditions – PET
findings may mimic relapse in the off-therapy setting: Thymic rebound hyperplasia
characteristically appears in the 6–12 months after completing the treatment and is
characterized by FDG avidity. Prospective studies on PET in pediatric patients will
improve our understanding of the optimal use of this method and the characteristics of
other nonmalignant conditions that may be considered in the differential diagnosis.
Prospective studies are currently under way on high-risk NHL patients and HL
patients with the aim at further investigating the role of PET in this setting [49, 103].
11.3.4 Pathology
The histopathological and immunohistochemical evaluations are fundamental for the

diagnosis of NHL and HL, but they should be completed with the genetic and molecu-
lar profiling of each histotype. The currently used histopathological classification is
based on the latest version of the WHO classification of lymphoproliferative diseases.
Non-Hodgkin Lymphoma The main histotypes are mature B-cell NHL, precursor
T-cell or B-cell NHL, and anaplastic large cell NHL
• B-cell NHL: These comprise Burkitt lymphoma and diffuse large B-cell lym-
phoma and primary mediastinal large B-cell NHL which is typical in adolescent
females. Burkitt lymphoma has a morphological appearance of a “starry sky”
due to histiocytes and macrophages coexisting among the blasts. Cytologically,
this disease consists of type L3 cells according to the FAB classification, with a
very high mitotic index (>90 %). The cells express surface immunoglobulins (Ig)
and are positive for several markers, including CD19, CD20, CD22, CD79a, and
often CD10. TdT is negative. Large B-cell lymphoma expresses a similar pheno-
type, but CD10 may be negative, and some patients do not express surface Ig.
Mediastinal large B-cell NHL is frequently characterized by sclerosis, and it is
often CD30 positive so that differential diagnosis with HL is possible.
• Lymphoblastic lymphoma (LBL): It has a cytological picture similar to lympho-
blastic leukemia: the cells have a high nucleus/cytoplasm ratio and finely dis-
persed chromatin. The most relevant feature for diagnostic purposes is TdT
expression, since no more than 5 % of LBLs are TdT negative. The majority of
LBLs are also CD99 positive. Approximately 80 % of LBLs derive from T cells
and variably express markers that can be traced back to thymic ontogenesis,
including CD7, CD2, CD5, CD1, CD3, CD4, and CD8. Precursor B-cell LBLs
express such markers as CD19, HLA-DR with CD10, but not surface Ig.
• Anaplastic large cell lymphoma (ALCL): It includes several morphological vari-
ants, although the so-called common type accounts for approximately 70 % of
cases. Differential diagnosis with HL is sometimes difficult. Typically, ALCL is
positive for CD30, EMA, T markers, and very often ALK, while it is negative for
CD15.
Hodgkin Lymphoma
• It includes:
• Classic HL (nodular sclerosis, mixed cellularity, lymphocyte depleted, lympho-
cyte rich)
• Nodular lymphocyte-predominant HL
The typical cell of HL is the Reed–Sternberg (RS) cell, which is binucleated or

multinucleated, with evident nucleoli immersed in a reactive type of cell matrix
(lymphocytes, granulocytes, eosinophils, macrophages). Hodgkin cells are almost
always CD30 positive, and they frequently express CD15; they are negative for
T-cell markers but sometimes positive (in approximately 20 % of cases) for CD20.
The most common form is nodular sclerosis subtype.
NHL The treatment of NHL is based essentially on polychemotherapy. The role of

surgery is generally limited to the diagnostic phase (biopsy) or for assessing resid-
ual tumor. Radiotherapy (RT) is not used in the frontline treatment. The use of
204 M. Podda et al.
prophylactic irradiation of the central nervous system for lymphoblastic lymphoma

has been abandoned.
The treatment must be designed to obtain a rapid and complete remission and
can be summarized in three phases:
Induction phase Polychemotherapy comprising cyclophosphamide, vincristine,

adriamycin asparaginase, and corticosteroids, aiming for a complete
remission in 4–6 weeks
Consolidation Use of high-dose methotrexate and/or cytosine arabinoside to consolidate
phase the complete remission
Maintenance phase Cyclic administration of various antimetabolites
HL Treatment is based on a combination of chemotherapy and RT, according to

the stage of the disease. Efforts are currently being made to reduce the dose of RT
in order to contain late effects. Because of the improvements in the prognosis, more
attention has to be paid to the toxicity of combinations of chemo- and radiotherapy:
The goal of undergoing studies is to maintain a high event-free survival while
reducing the use of alkylating drugs and the total dose of RT. As a part of the follow-
up, iatrogenic sequelae should be investigated, i.e., hormonal status, organ function
(lung, heart, kidney, liver), fertility, and hematological disorders.
11.4 Soft Tissue Sarcomas: Rhabdomyosarcoma
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in pediatric

age. It accounts for approximately 4–5 % of all childhood tumors, with approxi-
mately 200–250 new cases a year in Italy. It is a highly aggressive neoplasm, com-
prising cells of mesenchymal origin differentiating into striated muscle. Its incidence
peaks at around 2–3 years of age, with a second peak around 15–19 years old. The
male gender is slightly more affected [88]. There is a known association with con-
genital malformations, particularly when they involve the genitourinary tract, and
with other conditions such as the Li–Fraumeni and Beckwith–Wiedemann syn-
dromes and neurofibromatosis type 1 [5].
RMS may potentially occur anywhere in the body, but the sites most often affected
are the head and neck (40 %), the genitourinary tract (20 %), and the limbs (20 %).
The site is an important prognostic factor and influences the therapeutic strategy.
In approximately 20 % of cases, there are already metastases by the time RMS is
diagnosed. The disease metastasizes mainly to the lungs and less frequently to the
skeleton and bone marrow. There are lymph nodes involved in 20 % of cases, particu-
larly in tumors located in the retroperitoneum, lower limbs, and genitourinary tract.
11.4.3 Diagnostic Workup and Staging
Histological examination (on open or Tru-Cut biopsy material) is essential to the

diagnosis.
Local staging demands the use of axial CT and/or MRI with a contrast agent,
depending on the site of origin of the tumor (Fig. 11.1). Chest CT scanning, bone
scintigraphy with 99Tc, abdominal ultrasound, and bone marrow aspirates and biop-
sies are needed to stage remote dissemination. Lumbar puncture is also required in
parameningeal sites.
The application of FDG-PET appears to be attracting growing interest, but the
method is still under study in this setting. FDG-PET may be particularly useful for
the staging and reassessment of RMS occurring at certain sites, such as the parame-
ningeal, that are often not amenable to surgery. In such cases, using FDG-PET in
combination with MRI may orient the clinician’s actions at the end of the frontline
treatment phase, also in relation to the presence or absence of any significant meta-
bolic uptake [89].
The longest-standing staging systems are the ones proposed in 1972 by the North
American Intergroup Rhabdomyosarcoma Study Group (IRSG, for postoperative
staging) and the TNM (for clinical–radiological staging) [48]. The latest staging
systems also consider relevant prognostic parameters, such as histology, the site of
onset of the disease, and the patient’s age.
The site of the disease has an acknowledged role, and RMS developing within the
orbit and genital tract or at paratesticular sites have a generally better prognosis,
while a worse prognosis is associated with the limbs, parameningeal sites, the blad-
der and prostate, and “other sites”, such as the trunk. The prognosis is of intermediate
severity for RMS of the head and neck (other than the parameningeal) or genitouri-
nary tract (not involving the bladder or prostate). Age also seems to have a prognostic
significance, with patients under 10 years old usually having a better prognosis [54].
11.4.4 Pathology
RMS can be divided into two main histotypes: the embryonal (ERMS), which
accounts for approximately 75–80 % of all RM, and the alveolar (ARMS), in the
other 20–25 % of cases. A botryoid subtype of ERMS develops typically in the hol-
low organs and especially the vagina, bladder, and nasopharynx. ARMS has a char-
acteristic translocation – t(2;13)(q35;q14) or t(1;13)(p36;q14) – involving the
PAX3/PAX5 and FKHR genes responsible for regulating transcription [83].
Immunohistochemical investigations document positivity for proteins regulating
muscle differentiation, and particularly cytoplasmic positivity for desmin, and
nuclear positivity for MyoD1 and myogenin (Myf4) [87].
The currently used international classification distinguishes between the sub-
types on the strength of the morphological features of the disease and their prognos-
tic significance. Botryoid and ERMS have an intermediate/favorable prognosis,
while the alveolar histotype has a worse prognosis.
206 M. Podda et al.
The coordinated use of surgery, chemotherapy, and radiotherapy has gradually led
to an improvement in the chances of survival for patients suffering from localized
RMS, and nowadays, 70 % of patients are candidates for cure.
Surgery The goal of surgery is complete tumor resection with free margins (R = 0)
[100]. Whenever this is unfeasible already at the time of diagnosis or when surgery
exposes a patient to a high risk or certain damage, surgery may be limited to biopsy
alone (open or Tru-Cut) because RMS is a highly chemo- and radiosensitive
disease.
Radiotherapy RMS is a radiosensitive cancer, so radiotherapy has an important

role in local disease control. For some sites (parameningeal sites and prostate), it is
the only local treatment modality because surgery would inevitably be demolitive.
The doses commonly used are around 40–50 Gy [98].
Brachytherapy (using sources of Ir-192 and Cs-137) has a role in cases of RMS
located in the genitourinary tract and at cervicofacial sites.
The risk of late side effects, particularly evident in children (growth retardation,
skeletal malformations, cognitive impairments, endocrine disorders), needs to be
considered, and the so-called total burden of therapy should be borne in mind when
establishing the treatment plan [86, 108].
Chemotherapy Chemotherapy has considerably modified the natural history

of RMS, proving highly effective in controlling micro-metastases and enabling
significant volume reductions in both the primary tumor and any remote
metastases.
The drug combinations currently used (“gold standard”) are vincristine, ifos-
famide, and actinomycin D (the IVA protocol) [36] or the American alternative, in
which cyclophosphamide is used instead of ifosfamide (the VAC protocol). This
approach enables objective responses to be achieved in 75–80 % of cases. The dura-
tion of the treatment varies from 6 to 12 months.
Other drugs with a documented activity against RMS are the topoisomerase I
inhibitors (topotecan and irinotecan), which have achieved response rates in
excess of 40 % in previously untreated patients, and vinorelbine, a semisynthetic
vinca alkaloid that has demonstrated a good activity associated with a limited
toxicity [16].
After completing their treatment, patients with RMS must be followed up care-
fully, partly because of the risk of recurrences and partly to monitor any side effects
of the treatments they have received.
Recurrences are more likely to occur in the first 3 years after the primary RMS
was diagnosed, while they are rare beyond 5 years. They are local recurrences in
60 % of cases.
11.5 Non-Rhabdomyosarcoma Sarcomas (“Non-Rhabdo”)
“Non-rhabdo” soft tissue sarcomas form a heterogeneous group of malignant mes-

enchymal neoplasms that represent approximately 3–4 % of all tumors occurring in
pediatric age and adolescence. The neoplasms in this group differ from one another
in biological characteristics and clinical history, and – apart from a few exceptions,
such as infantile fibrosarcoma – they are diseases more typical of adults (the so-
called adult-type soft tissue sarcomas [35]). The histotype most often encountered
is synovial sarcoma (Fig. 11.2), which has a peak incidence between 15 and 30
years of age.
Although it may develop in virtually any part of the body, the limbs are the most
commonly affected site of this tumor.
The disease’s clinical behavior, and particularly its tendency to develop hema-
togenous metastases (generally to the lung), varies in relation to the histotype and
the tumor’s degree of malignancy [106].
The diagnosis can be established on incisional or Tru-Cut biopsies.
Local staging demands MRI with a contrast medium and/or axial CT scanning,
while chest CT scans (and sometimes abdominal and brain CT scans for certain
histotypes) and possibly bone scintigraphy are used for staging remote disease
11.5.3 Pathology
The histological classification of sarcomas of the soft tissue relies on the line of cel-
lular differentiation, i.e., on a comparison between the tumor’s cell line and the
Fig. 11.2 Most frequent histotypes of non-rhabdomyosarcoma sarcomas

208 M. Podda et al.
corresponding normal cell line. The histological diagnosis is necessarily based on

findings obtained using traditional optical microscopy and immunohistochemistry
but also relies increasingly nowadays on site genetics and molecular biology, used
to identify chromosomal and molecular rearrangements specific to the various
sarcomas.
The treatment of (pediatric or adult) patients with soft tissue sarcoma is rather com-
plex. It demands an integrated, multidisciplinary approach that takes all possible
therapeutic options – including surgery, radiotherapy, and chemotherapy – into
account.
Surgery This is the core treatment for this condition. Every effort must be made
to ensure that any surgery is radical (with oncologically free surgical margins)
and conservative (in both anatomical and functional terms), whenever possible
[46].
Radiotherapy This is indicated for tumors that are unresectable or have undergone
marginal surgery, especially in the case of sarcomas of high-grade malignancy or
for high-grade (G3) sarcomas greater than 5 cm in diameter that have been widely
resected. The role of radiotherapy for sarcomas of low-grade malignancy (which are
less sensitive to radiation) is more debatable.
Chemotherapy While the role of surgery and radiotherapy for soft tissue sarco-
mas is well established, the part that chemotherapy can play is more uncertain.
Systemic treatment is important, however, for high-grade (G3) tumors and those
larger than 5 cm in size because they feature a strong tendency to develop remote
metastases [41]. A combination of ifosfamide–doxorubicin is the solution most
often used. Other drugs (gemcitabine, docetaxel, cisplatin, trabectedin, etoposide)
may be used for certain particular histologies.
The methods and timing of the follow-up depend on the risks associated with the
degree of malignancy, the tumor’s dimensions, and the radicality of surgery.
Follow-up is always needed to check for possible sequelae of treatments (fibro-
sis, lymphedema, growth retardation in irradiated regions, endocrine damage, sec-
ond tumors).
11.6 Bone Sarcomas
Tumors involving the bone form a group of neoplasms with various presenting clini-
cal features, radiological appearances, and histopathological characteristics. They
mainly affect patients in the second and third decades of life and essentially consist
of osteosarcoma and the Ewing sarcoma family tumors (ESFT).
11.6.1 Osteosarcoma
11.6.1.1 Epidemiology and Etiology

Osteosarcoma (OS) is the most common primary malignancy occurring in the bone,
accounting for 60 % of all tumors. It is rare below 5 years of age and above 50 years
of age. It has a peak incidence in adolescence, coinciding with the time when the
body is growing the most. The annual incidence of OS is 2–3 cases per million
population. Males are more affected than females, with a male-to-female ratio of
1.5:1.
Ionizing radiation is considered a risk factor (the risk of an OS developing in an
irradiated body region being 2000 times higher than usual). Other risk factors
include (1) prior hereditary retinoblastoma (the RB oncogene); (2) Li–Fraumeni
syndrome (the p53 oncosuppressor is found mutated in 3–4 % of all cases of OS);
and (3) Bloom, Werner, and Rothmund–Thomson syndromes and Paget’s disease
(2 % of patients with OS).
11.6.1.2 Clinical Presentation

The clinical features of OS usually include a swelling that rapidly increases in size,
with inconstant and increasingly severe pain, and functional impotence, but the pre-
senting sign may sometimes be a pathological fracture. The disease usually devel-
ops on a level with the metaphysis of a long bone, and the neoplasm affects the knee
(distal femur or proximal tibia) in 75 % of cases.
11.6.1.3 Diagnostic Workup and Staging

For all patients presenting with soft tissue swelling and persistent pain, it is essential
to obtain an X-ray of the skeletal segment involved. In the majority of cases of OS,
the radiographic picture is characterized by cortical bone erosion and elevation of
the periosteum (bone spicules → Codman triangle), soft tissue swelling, and medul-
lary cavity erosion. There may also be evidence of calcification (“sunburst”) in the
surrounding soft tissues. The lesion may appear sclerotic (osteoblastic; 45 % of
cases), lytic (osteolytic; 30 % of cases), or mixed. Standard radiology needs to be
completed with contrast-enhanced MRI and/or a CT scan to better assess the neo-
plasm’s locoregional extent and check for any skip metastases (intramedullary
spread), which occurs in approximately 20 % of patients. Staging also requires
chest CT and bone scintigraphy with 99Tc.
FDG-PET does not yet have a firmly acknowledged role. It provides information
on the metabolic state of the disease, which correlates with the risk of necrosis after
chemotherapy. Taken together with the other radiological investigations, it may help
in the planning of surgery. It may also help to discriminate between disease and the
sequelae of surgery or artifacts of metal prostheses. On the other hand, it lacks the
sensitivity of scintigraphy with 99Tc in revealing skeletal metastases [89].
In 15–20 % of patients, synchronous metastases are identified at the time of
diagnosis; they involve the lungs in the majority (85 %) of cases [29].
Alkaline phosphatase levels, tumor volume, and tumor site are of prognostic sig-
nificance (the prognosis being worse for axial sites, i.e., the pelvis, spine, chest), and
210 M. Podda et al.
so are signs of necrosis after chemotherapy, evidence of metastases and their loca-
tion, number and resectability, and also P-glycoprotein (PgP) expression [3, 8, 71].
When a malignant bone neoplasm is suspected, the histological assessment
should be handled wherever possible by the orthopedic oncology center that will
subsequently perform any surgery.
Biopsies may be obtained by means of multiple Tru-Cut procedures or an open
biopsy (longitudinal incision), taking care to avoid contaminating the surrounding
tissues.
11.6.1.4 Pathology
Osteosarcoma is a malignant neoplasm characterized by the proliferation of neo-
plastic cells producing an osteoid matrix in a sarcomatous stroma.
Cases of classic or conventional high-grade OS (G3–G4) can be classified as
osteoblastic (in 50 % of cases), chondroblastic (in 25 %), or fibroblastic (in the
remaining 25 % of cases). Telangiectatic OS (3 %), small-cell, superficial high-
grade, and secondary OS are more rare.
11.6.1.5 Treatment and Follow-Up

The treatment for osteosarcoma involves a succession of chemotherapy, surgery,
and chemotherapy. This sequence is adopted to first shrink the tumor mass in order
to enable conservative surgery, wherever possible, and then to ensure the timely
treatment of micrometastases. It is also fundamentally important to assess the
degree of necrosis according to Huvos [44, 50].
The standard treatment for localized OS relies on the MAP protocol (high-dose
methotrexate + adriamycin + cisplatin), usually for a total period of approximately 9
months [42]. Other drugs that have a certain documented activity in this disease are
ifosfamide, VP16, cyclophosphamide, gemcitabine, and docetaxel. The use of mye-
loablative therapies has not produced any significant results [33, 51].
Osteosarcoma has always been considered a neoplasm in which the immune
system has a part to play. Hence, the use in several studies – in association with
chemotherapy – of molecules such as IL-2 and IFN-alpha. More recently, the
immune stimulant mifamurtide has been used for localized osteosarcoma after sur-
gery [74].
Surgery has a crucial role and necessarily involves en bloc tumor resection with
ample margins and removal of the tissue potentially affected by any previous biopsy
procedures. Conservative surgery can be performed in 90–95 % of cases. The recon-
struction options vary and are continuously evolving. They include extendable
metal prostheses that can be adapted as the child grows, osteoarticular allografts,
vascularized fibula, and combinations of metal prostheses with allografts. Whenever
conservative surgery is unable to guarantee oncologically adequate margins, it is
always essential to consider a demolitive procedure (amputation, disarticulation,
gyroplasty) because of the high risk of this disease recurring and the corresponding
very poor prognosis.
It is particularly worth mentioning the matter of surgery for metastases. If a met-
astatic lesion is considered operable, it should be removed because the chances of
cure in cases of metastatic disease rely on the combined use of chemotherapy and
surgery. Wedge resections for pulmonary metastases should be encouraged, accord-
ing to methods and timing established by the various centers [12, 85].
Radiotherapy only has a secondary role and should be reserved for selected
cases, in the absence of other therapeutic options. Radiotherapy for OS demands the
use of high doses (>60 Gy), often with particular fractionations (hypo- or hyperfrac-
tionation), and is used in cases of unresectable tumor, after inadequate surgery, and
for palliation or pain control [62]. There has been some interest in the use of carbon
ions and protons.
Metabolic therapy has been used in patients with metastatic disease and bone involve-
ment, administering high doses of samarium153-EDTMP (ethylenediamine tetrameth-
ylene phosphonate, 30 mCi/kg) and subsequently reinfusing the circulated hematopoietic
progenitor cells; this has achieved a fairly good pain control in some cases.
In the absence of metastases at diagnosis, the prognosis for patients suffering
from localized osteosarcoma is good, with 3-year event-free survival rates of 70 %.
For metastatic disease, the prognosis is unfavorable in cases of multiple skeletal or
lung metastases that cannot be removed surgically.
Patients with osteosarcoma must be followed up for at least 10 years, because the
disease is known to recur even very late. Patients must also be carefully monitored
for the possible risks of cardiotoxicity, neurosensory hearing impairment, altered
renal function, osteoporosis, arthromuscular disorders due to pathological loading
skeletal deformities, and prosthesis rupture/damage.
11.6.2 Ewing Sarcoma

After osteosarcoma, Ewing sarcoma is the malignant bone tumor most often seen in
childhood and young adults. It has a peak incidence in the second decade of life and
a slight predilection for the male gender beyond puberty. It accounts for approxi-
mately 20 % of all primary bone neoplasms and 15 % of those occurring in child-
hood. It is rarer than osteosarcoma, with an incidence of 2 cases per million children
a year. In approximately 50 % of cases, the disease develops in the axial skeleton
(mainly the pelvis and rib cage), and the most often affected long bone is the femur.
The etiology of Ewing sarcoma is unknown.
11.6.2.2 Clinical Presentation

The initial symptoms are characterized by pain (which may have been present even
for several months before the condition is diagnosed) and by swelling involving a
bone segment, which is not always readily noticeable. Since Ewing sarcoma can
develop at any site, the symptoms may relate to the impairment of a structure or
organ adjacent to the tumor.
By the time they are diagnosed, 15–30 % of patients already have metastases to
the skeleton, lungs, or lymph nodes. When the disease is disseminated, there may be
systemic signs such as fever, weight loss, and an impaired general state of health.
212 M. Podda et al.
With modern multimodal regimens, consisting of local surgery and/or radiother-

apy plus intensive systemic chemotherapy, survival is achievable for ∼70 % of
patients with localized disease [90]. The primary site appears to have prognostic
significance [27], the prognosis being worse for axial sites, which are rarely ame-
nable to radical surgery.
11.6.2.3 Diagnostic Workup and Staging

For the time being, Ewing sarcoma is not classified in stages; it may be localized or
metastatic.
Diagnostic and staging tests:
• Histology.
• Standard X-ray of the skeletal segment affected: The lesion is generally osteo-
lytic, destroying the normal bone pattern and interrupting the cortical compo-
nent. If located in the long bones, it may become evident from a characteristic
periosteal reaction in overlapping sheets (the so-called “onion skin” effect),
though this picture is not pathognomonic for Ewing sarcoma; structural altera-
tions occurring in flat or small bones have no particular radiological features.
• MRI and/or CT to assess the local extent of the neoplasm.
• Chest CT to rule out lung secondaries.
• Bone scintigraphy to rule out skeletal metastases.
• Bone marrow aspirates and biopsies to exclude bone marrow involvement.
The 2012 National Comprehensive Cancer Network guidelines suggest PET or

bone scan (or both) for initial staging purposes. The Children’s Oncology Group
Bone Tumor Committee suggests chest CT and MDP bone scan and recommends
FDG-PET, particularly if the primary bone tumor is not visible on a bone scan.
Bone marrow aspirates or biopsies are used to complete the staging by imaging.
11.6.2.4 Pathology
Cytogenetic studies have demonstrated a typical translocation t(11:22) (q24:12)
[30]. Like the pPNET neoplasms, osseous and extra-osseous Ewing sarcomas share
much the same morphological, immunophenotypic, cytogenetic, molecular, and
biochemical features, confirming the hypothesis that these neoplasms have the same
neuronal origin.
11.6.2.5 Treatment
Ewing sarcoma is a radio- and chemosensitive neoplasm. The main goal of therapy
is to obtain a complete and definitive local control, preserving the function of the
affected body segment as much as possible and preventing the disease from
spreading.
The role of surgery for this disease is constantly evolving. At one time, the
majority of patients were treated with surgery alone and had little chance of cure.
Nowadays, the availability of systemic neoadjuvant treatments capable of inducing
a good regression of the primary tumor and radiation treatments capable of ensuring
a good local disease control have made conservative surgery possible in the majority
of cases.
Most protocols consider histological response to neoadjuvant therapy [2] as
a prognostic factor, and the intensity of adjuvant chemotherapy is based on the
degree of histological response as well as on the presence of metastases at diag-
nosis. If the primary neoplasm cannot be resected without mutilating surgery, or
because of the site involved (e.g., lesions in the pelvis), the radiological evi-
dence of response should help the oncologist in the choice of appropriate
therapy.
CT scanning and MRI are also used to assess the reduction in the tumor’s size as a
criterion for examining response to therapy, but the dimensions of the tumor may not
change early in the course of treatment, and this limits the predictive value of these
methods. FDG-PET/CT may prove to be an ideal noninvasive method for assessing
tumor response and orienting the further management of these neoplasms [26].
11.7 Neuroblastoma
Neuroblastoma is a malignant neoplasm of the autonomic nervous system that

originates from the primitive neuroectodermal crest cells. In two of the three cases,
the mass develops in the abdomen, starting from the paravertebral ganglia or the
adrenal glands, causing symptoms relating to organ compression in the abdominal
cavity; in 20 % of such cases, the neuroblastomas originate from the paravertebral
ganglia of the posterior mediastinum, giving rise to severe respiratory symptoms;
in some cases, however, there may be an incidental finding. Less frequently, neu-
roblastomas may develop at neck level (where they become manifest as adenopa-
thies or Bernard–Horner syndrome) or in the pelvis (causing dysuria and/or
constipation). The sites most often affected by metastases are the bone and bone
marrow. The presenting symptoms are often those relating to the tumor’s dissemi-
nation, such as fever, anorexia, pallor, bone pain, periorbital ecchymoses, and pro-
ptosis. In approximately 50 % of cases, the disease is already metastatic on
presentation.
Neuroblastoma is the third most common pediatric tumor after leukemia and neo-
plasia of the central nervous system. It is the solid tumor most often identified in
patients under 5 years old, with approximately 1200 new cases diagnosed annually
in the United States and Europe.
The mean age at diagnosis is around 2 years, and 90 % of cases are diagnosed
before 6 years of age, while this neoplasm becomes exceptional in adolescents and
adults. Some cases may be diagnosed before birth. The male/female ratio is 1:1.3.
No etiological, environmental, physical, chemical, or viral agents have ever been
correlated with the onset of neuroblastoma.
214 M. Podda et al.
11.7.2 Biological–Molecular Characterization
The last two decades have seen a considerable improvement in our understanding of
the biological characteristics of neuroblastoma, and chromosomal alterations have
been identified in the neuroblastoma cells that correlate with the patient’s
prognosis:
• MYCN amplification: MYCN is the first neuroblastoma-specific molecular

marker to be identified as an unfavorable prognostic factor, irrespective of the
patient’s age and the stage of the disease; this is an oncogene that maps to 2p24.
MYCN amplification is found in approximately 20 % of cases.
• 1p deletion: This occurs in 30 % of cases, usually associated with MYCN ampli-
fication, and it too has an unfavorable prognostic significance.
• Trisomy or polysomy of portions of 17q: This is another predictor of aggressive
disease.
• 11q deletion: This has been associated with an unfavorable prognosis in local-
ized forms and in stage IV-S cases without MYCN amplification.
Clinical stage is currently the most significant and clinically relevant prognostic
factor. In 2009, the International Neuroblastoma Risk Group (INRG) Project
proposed a new staging system designed for the purpose of tumor staging before
any treatment [77]. While the International Neuroblastoma Staging System
(INSS) [14] (Table 11.2) is currently the most often used system and focuses on
pathological findings after surgery, the INRG Staging System (Table 11.3)
focuses on imaging findings. This new staging system is not intended as a sub-
stitute for the INSS, and it is recommended that both systems be used in
parallel.
Table 11.2 Staging according to the International Neuroblastoma Staging System (INSS)
Stage I Localized tumor, complete gross excision
Stage Localized tumor, gross residual disease
IIA
Stage Localized tumor + ipsilateral nodes (resectable or not)
IIB
Stage III Tumor crosses midline and is unresectable +/− regional nodes or localized
tumor + contralateral nodes
Stage IV Distant dissemination
Stage <1 year with localized primary tumor + dissemination limited to the skin, liver, or
IV-S bone marrow (<10 % nucleated cells)
Table 11.3 Staging according to the International Neuroblastoma Risk Group Staging System
(INRGSS)
L1 Localized tumor not involving vital structures, based on a list of image-defined risk
factors and confined to one body compartment
L2 Locoregional tumor with the presence of one or more image-defined risk factors
M Distant metastatic disease (except stage MS)
MS Metastatic disease in children younger than 18 months with metastases confined to the
skin, liver, and/or bone marrow
Prognostic Factors The INRG Task Force has identified 7 factors as having statis-
tical significance in predicting patient outcome [23]: INRG stage, age, histology,
degree of differentiation, MYCN, ploidy, and 11q aberration.
The prognosis is more favorable in children under 18 months old [78] and/or
with localized disease. In adolescents and adults, the disease has a more indolent
behavior with even late recurrences and a less favorable prognosis [38].
Patients in stages I and II have an excellent prognosis, with disease-free survival
rates at 5 years in the range of 80–90 %. Patients in stages III and IV have a worse
prognosis, with 5-year disease-free survival rates of 40–60 % and 15–25 %, respec-
tively. Patients in stage IV-S have disease-free survival rates of 70–90 %.
Diagnostic Procedures Magnetic resonance (MR) or computed tomographic (CT)

images must always be obtained at the time of diagnosis for accurate staging. MR
imaging is recommended for patients with intraspinal disease.
To establish the extent of metastases in bone and bone marrow involvement
demands the use of both imaging and bilateral bone marrow aspirates and biopsy.
123I-mIBG scans are essential for the initial staging of neuroblastoma, as they
have a specificity of 85–96 % [70]. Metaiodobenzylguanidine score at diagnosis
may be prognostic: higher scores indicate a high body burden of tumor and have
been associated with a worse outcome in some studies.
Single-photon emission computed tomography enables a more accurate geo-
graphical localization of metastases and helps to differentiate them from physiolog-
ical areas of uptake.
There is a strong rationale to use 123I-mIBG scintigraphy in assessing
response to therapy too, as it is a very sensitive marker of unsuspected skeletal
and nodal disease and provides functional evidence of residual active tumor [13].
With the widespread use of therapeutic 131I-mIBG as a targeted radiopharma-
ceutical treatment for neuroblastoma – both in newly diagnosed and in relapsing
patients – diagnostic mIBG scans can ascertain patient eligibility for this treat-
ment modality.
There is strong evidence to support 123I-MIBG scintigraphy as the method of
choice for the noninvasive staging of children with neuroblastoma. PET imaging
using FDG has not proved superior to MIBG [70]. New candidates for use in PET
imaging (18F-DOPA, 68Ga-DOTATATE) are under evaluation, however, and will
be discussed elsewhere in this publication.
216 M. Podda et al.
The main questions that the oncologist asks the nuclear physician thus concern
diagnostics and staging but also to response to treatment and to exploring the feasi-
bility of radionuclide treatment in the event of a patient’s failure to respond to con-
ventional treatments.
11.7.4 Treatment
Nowadays, treatment for neuroblastoma is based on surgery, chemotherapy, immu-

notherapy, and radiotherapy. The approach is dictated by the risk of recurrence,
which depends on the patient’s age, the extent of the disease at diagnosis, and its
histological and biological characteristics.
Surgery Surgery plays a fundamental part in the treatment of neuroblastoma, at

diagnosis and after chemotherapy. The goals of immediate surgery are to remove
the tumor with a minimal morbidity, confirm the diagnosis, and obtain material for
biological studies. The importance of resection remains controversial in cases of
disseminated neuroblastoma [102, 117], but, considering the incidence of local
recurrences, the recommendation today is to attempt a radical or at least major
resection.
Chemotherapy Chemotherapy is certainly our most important therapeutic option

for the treatment of metastatic neuroblastoma and for initially inoperable localized
forms. In 50 % of cases, the disease is considered as high risk, and the treatment of
these patients involves associations of alkylating drugs, vinca and platinum deriva-
tives, epipodophyllotoxins, and doxorubicin, followed by myeloablative therapy,
and then maintenance with differentiating agents and immunotherapy.
Radiation Treatment Neuroblastoma is a radiosensitive tumor, but it cannot be

cured by radiotherapy. For the time being, radiotherapy is only indicated in patients
with a very poor prognosis, after completing chemotherapy and surgery.
Another radiotherapeutic approach is metabolic, using 131I carried by metaiodo-
benzylguanidine, a norepinephrine analog capable of entering the metabolic path-
way of the catecholamines and consequently being taken up by the neuroblastoma
cells.
11.8 Thyroid Cancer
Thyroid cancers are the most common tumors of the endocrine glands in childhood
and adolescence, but these solid tumors are rare in this age group.
In childhood, the vast majority (more than 90 %) of follicular cell-derived thy-
roid cancers are differentiated thyroid carcinomas [28], i.e., papillary and follicular
carcinomas. Poorly differentiated and undifferentiated (anaplastic) carcinomas are
both practically nonexistent.
11.8.1 Differentiated Thyroid Carcinoma

Among the DTC, papillary thyroid carcinoma (PTC) is the most common type, with
ionizing radiation apparently an important causal factor [96].
Accordingly, a steep rise in the incidence of PTC was observed in the young
population following the 1986 Chernobyl Nuclear Power Plant accident. Children
treated with radiation therapy to the neck are also at risk of subsequent PTC [7].
The preponderance of females affected in the literature is likely to be related to
the thyroid gland’s estrogen sensitivity. In prepubertal children, in fact, the influ-
ence of gender is not so clearly detectable [52].
Follicular thyroid carcinoma (FTC) is generally of the minimally invasive type,
the widely invasive counterpart being exceptional.
11.8.1.2 Clinical Presentation and Diagnosis

PTC and FTC differ in their presenting features and biological behavior. Both may
present as a thyroid mass, and lung and bone metastases are possible. Nodal metas-
tases are very common in PTC but practically absent in FTC. Children with DTC
most often present with an asymptomatic thyroid mass or palpable cervical
lymphadenopathy.
No preoperative markers can distinguish DTC from benign nodules, but the labo-
ratory assessment of thyroid function and serum thyroglobulin is still useful.
FNAB has not been used extensively in young patients, though a meta-analysis
demonstrated that FNAB is a sensitive diagnostic test, proving useful as a tool for
diagnosing malignancy in pediatric thyroid nodules [107].
11.8.1.3 Special Considerations

Several studies have shown that DTC in pediatric patients differs in presentation and
outcome from the corresponding condition in adults. This malignant disease is asso-
ciated with a more locally aggressive behavior and more frequent distant metastases
in childhood than in its adult counterpart [24]. Recurrence rates tend to be higher in
the pediatric population too. The cause-specific mortality for DTC nonetheless
remains low.
11.8.1.4 Therapy
The management strategies for DTC in children are still being debated. In general,
the approach based on radical surgery (thyroidectomy plus lymph node dissection)
followed by radioiodine therapy and TSH suppression aims to control both macro-
and microscopic diseases. This strategy has been borrowed from trials in adult
patients. Considering the potential long-term sequelae of such treatment, a more
conservative approach might also be considered for selected pediatric patients. This
latter strategy only aims to control macroscopic disease with limited surgery
(hemithyroidectomy and limited neck dissection) and involves no radiotherapy, but
it is always followed by TSH suppression. Given the excellent (almost 100 %) over-
all survival with both approaches, the benefits of these two options have to be
218 M. Podda et al.
carefully weighed in each patient because no prospective studies are currently avail-
able that can provide definite evidence in favor of one or the other strategy.
Surgery The development of a standard strategy for the treatment of childhood

thyroid cancer suffers from the same problems as in the case of other rare pediatric
tumors, i.e., reliance on retrospective studies given the lack of prospective clinical
trials [25, 105].
The vast majority of patients undergo total thyroidectomy, with or without lymph
node dissection.
Advantages of this radical approach are:
• An upgrading of the progression-free survival (PFS) and overall survival (OS)

rates.
• Ablative radioiodine therapy can be administered.
• Metastases can be detected sensitively using whole-body scintigraphy.
• Thyroglobulin can be used as a sensitive marker of relapse.
• Numerous children with PTC have multifocal disease, so all thyroid tissues
potentially at risk of containing multiple neoplastic foci are removed [113].
A more conservative approach has been considered for selected patients with
tumors limited to one lobe, with or without clinical evidence of monolateral nodal
metastases [67]. The main argument in favor of a conservative approach lies in the
excellent prognosis for DTC in children and adolescents, despite an often more
advanced stage at presentation and a more aggressive clinical course [22, 28].
The use of more aggressive procedures, especially in children under 16 years old,
correlates closely with a greater morbidity (permanent hypoparathyroidism and
recurrent nerve palsy) [59, 110]. The minimal approach involves hemithyroidec-
tomy, i.e., lobectomy plus isthmectomy. The most appropriate treatment will con-
tinue to be debated as long as there are no prospective trials investigating the
different therapeutic options. For a conservative approach to be adopted, the pathol-
ogist expert in the diagnosis of pediatric thyroid carcinomas has a crucial part to
play.
Radioiodine Therapy and Hormone Manipulation After a radical surgical

approach has been used, the radioactive isotope 131I can be administered for
the selective irradiation of remnant thyroid tissue, microscopic foci of carci-
noma, and distant metastases. The first ablative radioiodine therapy (RIT) after
total thyroidectomy is for adjuvant purposes, to eliminate all remaining thyroid
tissues and improve the sensitivity of thyroglobulin assay and whole-body scin-
tigraphy during the follow-up. The aim of suppressing TSH secretion
(TSH < 0.1 mU/l) is to prevent any growth of hidden microfoci, residual tumor,
or metastases. The RIT activities used vary from 50 MBq/kg for ablation pur-
poses to 100 (−150) MBq/kg for metastatic disease [39]. It is advisable to moni-
tor lung function to check for radiation-induced pulmonary fibrosis, which is a
rare sequela of RIT.
11.8.2 Medullary Thyroid Carcinoma
Medullary thyroid carcinoma (MTC) arising from the parafollicular C cells is asso-
ciated with inherited tumor syndromes. The multiple endocrine neoplasia (MEN)
types IIA and IIB and familial medullary thyroid carcinoma (FMTC) are all charac-
terized by bilateral multifocal MTC, invariably against a background of C-cell
hyperplasia (the inherited predisposing abnormality).
MTC is particularly aggressive in patients with MEN 2B and may occur even in
infancy [116]. Different germline point mutations of the rearranged during transfec-
tion (RET) proto-oncogene are involved in the pathogenesis of MTC and MEN 2,
with different consequences for the management of the children affected [94].
More than 90 % of patients with MEN 2B harbor de novo mutations in the RET
proto-oncogene. These index cases with no family history are at high risk of devel-
oping advanced MTC, and the associated mortality rate is high.
Calcitonin levels provide an accurate and sensitive marker for both the preopera-
tive diagnosis and the follow-up of MTC.
The most appropriate therapeutic option is radical surgical resection of all tumor
sites, since no curative medical therapy is available [57]. In recent years, targeted
therapy with small molecules such as tyrosine kinase inhibitors or RET kinase
inhibitors has been studied in clinical trials, achieving partial responses in up to
30 % of cases [60, 92]. The most important prognostic factor is clinical stage at
diagnosis. Patients with positive lymph nodes or distant metastases are at risk of
relapse and fatal outcome [6].
11.9 Melanoma
Melanoma is very rare in pediatric age, accounting for just 1–3 % of all pediatric
tumors. Several sources have identified a continuous increase in its incidence, how-
ever, at a rate of 2.9 % a year. In the United States, it is estimated that 300–420 new
cases of pediatric melanoma are diagnosed every year [84].
Pediatric melanoma may develop at any time. It can occur during intrauterine life
and throughout childhood and adolescence. We therefore speak of congenital mela-
noma (in cases diagnosed in the fetus or at birth), neonatal or infant melanoma
(from birth to 1 year of age), childhood melanoma (from 1 year of life to puberty),
and adolescent melanoma (from puberty to 21 years old), the latter being the age
group most often affected [75]. Females are affected slightly more than males.
In some cases, melanoma may develop in patients who are predisposed (heredi-
tary melanoma). Such patients may have germ cell mutations affecting particular
genes (CDKN2A, Cdk4, MCR1) that are involved in the processes of apoptosis and
cell growth, and this gives them a high risk of developing the disease, even very
early in life. There are other predisposing or risk factors for pediatric melanoma: a
positive family history of melanoma, a history of frequent burns (more than three
220 M. Podda et al.
times before 20 years of age), very pale skin and hair, large congenital nevi, an
immunosuppressed state, dysplastic nevus syndrome, and xeroderma pigmentosum
(in which case the risk of developing a melanoma increases 2000-fold).
11.9.2 Clinical Presentation and Diagnosis
The most common clinical signs are a nevus that increases in size, bleeds, or changes
in color; pruritus, a subcutaneous mass; or an adenopathy. Approximately one in
two pediatric melanomas is amelanocytic and 30 % are nodular. The ABCD – asym-
metry, borders (irregular), color (variegated), and diameter (larger than 6 mm) – cri-
teria are helpful in the diagnosis of melanoma in pediatric age as in adults. Particular
attention should be paid to the differential diagnosis with Spitz nevus, which often
has an atypical appearance but a benign behavior. Suspect lesions must always
undergo histological examination. Pediatric melanomas are quite often diagnosed
late due to a common tendency to assume that melanoma does not occur in young
people. When melanoma is diagnosed, it is essential to perform an ample excision,
surgery being the mainstay of its treatment. Sentinel lymph node biopsy is recom-
mended for lesions > 0.75 mm thick (and it is indispensable for staging regional
lymph nodes). Various studies have documented a greater involvement of the
regional lymph nodes in pediatric age (with sentinel lymph node positivity in
25–60 % of pediatric patients as opposed to 20–25 % of adult patients). Complete
lymphadenectomy is recommended in cases of sentinel lymph node positivity.
Staging investigations include ultrasound of the abdomen and lymph nodes and
chest X-ray or total-body CT scan and PET in some cases.
11.9.3 Therapy
Systemic treatment for advanced disease involves the use of immunotherapy (IFN-
alpha-2b). Results achieved with chemotherapy are distinctly disappointing. In the
pediatric setting, there is also great interest in the use of novel target therapies with
biological drugs (vemurafenib, anti-B-RAF; ipilimumab, anti-CTLA4).
The overall survival rate at 5 years is approximately 70 % and seems to be better
for patients under 10 years of age (90 % at 5 years) and worse for patients between
10 and 14 years old (49 %). Unfavorable prognostic factors include a greater thick-
ness and lymph node metastases [35].
11.10 Wilms’ Tumor
Wilms’ tumor (nephroblastoma) is the primary renal neoplasm in pediatric age with
an incidence of 8.1 cases per million children under 15 years of age, with no
difference between genders. The mean age at diagnosis ranges from 42 to 47 months
for the unilateral forms, while it is around 30 months for the bilateral forms (5–7 %
of all cases). Familial forms have been described in 1–2 % of cases. Wilms’ tumor
can be associated with congenital malformations, such as hemihypertrophy, aniridia,
and genitourinary malformations. It has rare but characteristic associations with
Beckwith–Wiedemann syndrome (gigantism, visceromegaly, macroglossia, neona-
tal hypoglycemia), Denys–Drash syndrome (pseudohermaphroditism, glomerulo-
nephritis, or nephrotic syndrome), and WAGR syndrome (Wilms’ tumor, aniridia,
genitourinary malformations, and mental retardation).
The most common symptoms are abdominal pain, hematuria, and the finding of an
abdominal mass. The diagnosis may be established earlier as part of screening pro-
grams or during the follow-up for congenital malformation or syndromes.
• Blood chemistry and urine tests (anemia, micro- or macrohematuria)

• Abdominal ultrasound
• Abdominal CT or MRI
• Chest X-ray and chest CT scan (to rule out secondary pulmonary neoplasms)
• Histology
• PET: The role of FDG-PET in Wilms’ tumor has yet to be established. A recent
case report [91] describes its role in assessing response to chemotherapy (even in
cases with no evidence of significant dimensional changes on conventional
imaging) and in showing and to show potential correlations between different
SUVs and histopathological features (i.e., a marked increase in SUV is seen in
the high-risk anaplastic type of Wilms’ tumor).
Although FDG-PET scanning in patients with Wilms’ tumor requires more

extensive research, it appears to have a role in delineating the extent of disease,
especially at the end of first-line therapy. It can help to distinguish malignancies
from benign nephrogenic residuals, facilitating the planning of surgery and histo-
logical differentiation [89]. Another possible application for FDG-18-PET is in
assessing the extent of disease recurrences [9].
11.10.4 Pathology
Macroscopically, the neoplasm is surrounded by a pseudocapsule of connective tis-

sue. It often extends to the pelvis and more rarely to the ureter. It may also go
beyond the renal capsule, infiltrating the perirenal fat. A neoplastic thrombosis of
222 M. Podda et al.
the renal vein may reach the vena cava and even the right atrium. The regional, renal
hilar, and periaortic lymph nodes are involved in 15 % of cases.
Microscopically, this is an embryonal tumor containing variable proportions of
blastematous, epithelial, and mesenchymal cells. Anaplasia correlates with a less
favorable prognosis. In particular, diffuse (as opposed to focal) anaplasia is still a
decisive prognostic factor. The current classification of Wilms’ tumor is the one
proposed by the National Wilms Tumor Study Group.
The radiological differential diagnosis between the most common kidney tumors
(Wilms’ tumor, clear cell sarcoma, rhabdoid tumor, mesoblastic nephroma, renal
cell carcinoma) is not easy. As for the benign conditions, the differential diagnosis
might involve hydronephrosis, single or multilobular renal cysts, and renal abscess.
11.10.5 Treatment
The current approach to treatment involves the use of surgery in all cases and che-
motherapy for the majority of patients, with the exception of some extremely favor-
able, selected cases; the use of radiotherapy is more limited and less standardized.
The chances of cure are currently around 85 %.
Surgery Depending on the clinical–radiological features of a case and the experi-

ence of the center involved, surgery may be performed immediately or after neoad-
juvant chemotherapy. Surgery must include radical nephrectomy and lymph node
sampling (removing the regional, i.e., hilar, lymph nodes and the para-aortic and/or
paracaval lymph nodes ipsilateral to the tumor). Conservative surgery of the affected
kidney is only indicated in patients with bilateral neoplasms or in clinical situations
at greater risk of metachronous neoplasms in the contralateral kidney (e.g., in pre-
disposing syndromes).
Chemotherapy and Radiotherapy The chemotherapeutic protocol is established

according to the stage of the neoplasm and the presence or absence of anaplasia. The
most active drugs against Wilms’ tumor are actinomycin D, vincristine, adriamycin, and
cyclophosphamide. More recently introduced drugs, such as ifosfamide, etoposide, and
carboplatin, have proved effective in inducing remission in patients failing to respond to
the traditionally used drugs, in patients with anaplasia, and in the event of a recurrence.
Radiotherapy is used in cases with diffuse anaplasia and sometimes in Wilms’ stages I,
IV, and V without anaplasia, partly depending on response to chemotherapy.
11.11 Germ Cell Tumor (GCT)
Germ cell tumors account for 3 % of all pediatric malignancies and derive from
totipotent precursors of mature germ cells. They develop not only in the gonads but
also at other sites as a consequence of progenitor cells migrating along the dorsal
crest of the embryo.
The incidence of the most common GCT, sacrococcygeal teratoma (benign in
80 % of cases), is around 1/35,000 live births. GCTs typically have a bimodal
distribution, peaking at around 2 and 20 years of age; they have a predilection for
the female sex (3–4:1). Their etiopathogenesis is unknown. Some GCTs are
associated with genetic abnormalities, such as gonadoblastoma, which develops
in intersexual states (hermaphroditism) and in dysgenetic gonads. Mediastinal
GCTs have also been described in individuals suffering from Klinefelter
syndrome.
The presenting symptoms of the disease depend on the site of the neoplasm. The
most common sites are the ovary and testicles. The sacrococcygeal site is affected
less frequently, and GCTs involving the brain or retroperitoneal and mediastinal
regions are even more rare.
• α-Fetoprotein (αFP) and βHCG (β-subunit of human chorionic gonadotropin)

assay.
αFP is normally high in the fetus and drops gradually after birth, reaching normal
levels after 8 months. Its half-life is 5 days. βHCG has a plasmatic half-life of 24–36
h. αFP and/or βHCG levels are pathological in 90 % of cases of non-germinomatous
GCTs. αFP levels increase in tumors of the endodermal sinus and in embryonal
carcinoma. βHCG levels are always high in choriocarcinoma and in 70 % of GCTs
in general. In germinomatous GCTs, on the other hand, the increase of βHCG levels
is usually limited, to such a point that they are described as nonsecreting. Testing
markers can facilitate the diagnosis and should always be done before any treatment
is undertaken. Half-lives longer than normal and the persistence of pathological
values after surgery are indirect signs of metastases, occult disease, and/or nonradi-
cal surgery. A gradual reduction in marker levels is an indication of response to
treatment.
• CT/MRI of the primary tumor site.

• Chest CT scan (to rule out pulmonary secondaries).
• PET: There is no dedicated pediatric literature on the role of nuclear medicine in
GCTs, so most of the information available is drawn from experience with adults.
A recent study on adult GCT analyzed the utility of fluorine-18 fluorodeoxyglu-
cose ([18]F-FDG) positron emission tomography/CT (PET/CT) for restaging
patients suspected of recurrent disease or for assessing the effects of therapy. The
224 M. Podda et al.
authors concluded that (18)F-FDG-PET/CT has a high diagnostic accuracy for

restaging patients with malignant GCTs. It has an equally good diagnostic per-
formance in both seminomatous and non-seminomatous malignant GCTs [101].
According to another adult experience, PET can be used in restaging to distin-
guish between fibrotic residual masses and active disease (i.e., to distinguish
mature teratoma from scar tissue) [89].
11.11.4 Pathology
We can distinguish between:
• Malignant germinomatous germ cell tumors (MNGGCT), which tend to metasta-

size via the lymphatics and bloodstream, especially to the lungs. They include
(1) embryonal carcinoma, (2) tumor of the endodermal sinus or yolk sac, (3)
choriocarcinoma, (4) teratoma with a sarcomatous or carcinomatous malignant
component, and (5) mixed forms.
• Germinomas, which have a better prognosis; they metastasize mainly via the
lymphatics, while hematogenous metastases are rare. They include (1) semi-
noma (in the testicles), (2) dysgerminoma (in the ovaries), and (3) germinoma
(mediastinal or in the CNS).
11.11.5 Treatment
Surgery is the only treatment used for disease confined to the organ of origin and
amenable to total resection (stage I), whatever the site involved. Surgery is also
essential for removing lesions persisting after chemotherapy, be they metastases or
residuals of primary tumor.
For chemotherapy, the reference protocol is borrowed from adult oncology and
involves an association of cisplatin, etoposide, and bleomycin (PEB). With the
exception of germinomas, which are extremely radiosensitive, the role of radio-
therapy for pediatric GCTs is extremely limited.
11.12 Nasopharyngeal Carcinoma
11.12.1 Epidemiology
Nasopharyngeal carcinoma (NPC) is a very rare disease in childhood. Its inci-

dence varies widely from one region to another, reflecting interactions between
genetic and environmental factors, such as exposure to Epstein–Barr virus
(EBV) [11].
In the United States, the annual incidence of the disease in childhood is 0.1–
1.5/1,000,000/year, with a median age of 13 years at presentation.
Pediatric NPC is distinguishable from its adult counterpart because of its associa-
tion with EBV infection, undifferentiated histology, and high incidence of locore-
gional spread and distant metastases. The most common presenting sign is a mass
in the upper neck, which may already be quite large at diagnosis. The mass may
invade the skull base, so the cranial nerves are frequently involved as a result.
Frequent symptoms are headache, facial pain, and neck pain, lasting a median of 5
months before the diagnosis. Metastases may occur in the bones, lungs, liver, bone
marrow, and mediastinum [99]. The differential diagnosis must include upper respi-
ratory tract infections, non-Hodgkin lymphoma, Hodgkin lymphoma, rhabdomyo-
sarcoma, germ-cell tumor, and benign soft tissue lesions [111].
11.12.3 Diagnosis
11.12.3.1 Pathology
Type III or undifferentiated carcinoma (also known as lymphoepithelioma) is the
most common subtype in children.
11.12.3.2 Staging
• Clinical examination and endoscopy.
• Baseline blood EBV-DNA assay is useful for monitoring the disease’s response
to treatment and recurrences.
• Baseline lactic acid dehydrogenase test (indicative of a poor prognosis when
>500 IU/mL).
• MRI is the preferred imaging modality, used to evaluate the extent of locore-
gional disease, including nodal metastases and perineural involvement.
• CT should be useful to assess any bone erosion.
• Chest X-ray and bone scans are usually performed to detect distant metastases.
• FDG-PET seems to have an emerging role, alone or combined with CT scan.
It can provide semiquantitative information on the tumor’s functional activ-
ity and distinguish active tumor from scar tissue, but its role in pediatrics is
controversial. Some studies have found MRI superior to PET in assessing
primary tumor extent. There is a better concordance between PET and MRI
findings in nodal staging, but PET is reportedly more accurate in detecting
cervical lymph nodes than conventional imaging because MRI may overesti-
mate if based on dimensional criteria alone. On the other hand, some studies
have found FDG-PET unable to provide more information than MRI, because
of its lower spatial resolution and a higher false-positive rate, so its role with
respect to conventional imaging remains unclear. PET can nonetheless con-
tribute to detecting distant metastases and residual or recurrent disease.
Further prospective studies are needed to elucidate the clinical utility of
FDG-PET/CT, and future assessments on the feasibility of PET/MRI might
prove interesting [1, 19].
226 M. Podda et al.
11.12.4 Treatment and Prognosis
The treatment is generally extrapolated from adult patients’ guidelines and consists
of concomitant chemo- and radiotherapy. Although children and adolescents are
more likely to have advanced disease at onset, they generally have a significantly
better chance of survival than adults. Undifferentiated NPC is very sensitive to radi-
ation, so external beam radiation therapy has become the mainstay of treatment.
With radiotherapy alone, the 5-year survival ranges from 20 to 60 % in most pedi-
atric series. Trials have been run on several chemotherapy regimens in pediatric
populations in an effort to improve survival; the rationale behind concomitant
chemo- and radiotherapy is to eradicate local and occult metastatic disease by
means of a radiosensitization effect and the systemic effects of cytotoxic agents (the
regimens most used include cisplatin and fluorouracil, cisplatin plus epirubicin, and
bleomycin) [73], although the new conformational radiotherapy techniques,
treatment-related toxicity as growth retardation, dental problems, endocrine prob-
lem, ototoxicity, or second malignancies may be severe in younger individuals and
needs carefully monitoring. Immunotherapy with anti-EBV T cells may be another
promising approach to the treatment of EBV-related NPC [15, 20].
11.13 Retinoblastoma (RB)
Retinoblastoma is the most common intraocular neoplasm in pediatric age, account-

ing for 3–4 % of all malignant tumors in this age group. It has an incidence of 1 in
15–20,000 live births per year. In Italy, the estimated incidence is 32 cases a year.
The disease may be monolateral (in 70 % of cases) or bilateral (30 %), and unifocal
or multifocal. In 80 % of patients, it is diagnosed within the first 3 years of life,
while beyond 6 years of age, it occurs very rarely.
RB is a model of hereditary tumor in humans, but it may be sporadic or inher-
ited. A clearly hereditary, autosomal dominant transmission is identifiable in
10–15 % of unilateral retinoblastomas and in the majority of the bilateral forms.
Sporadic cases would be due instead to two somatic mutations. Since the Rb1 gene
involved in the genesis of RB plays a part in other neoplasms (and osteosarcoma in
particular), there is a risk of second tumors developing in long-term survivors of
hereditary RB.
The elements essential to the diagnosis are:
• A positive family history (10 %).

• Leukocoria (60 % of patients).
• Strabismus (20 % of patients).

• Glaucoma (secondary to multiple or very extensive neoplasms that cause an
increase in endocular pressure).
• Pupillary red reflex: When lacking, it is a sign of ocular disease that should be
urgently examined by an ophthalmologist; it is recommended that family pedia-
tricians test for this reflex during the periodical controls.
• Ophthalmoscopic examination (see above)

• Ocular ultrasound (to check for the presence/absence of a mass in the posterior
segment when the fundus is not visible)
• Cerebral, facial, and orbital CT (to assess the intra- and extraocular extent of the
neoplasm)
• Brain MRI (it is the method of election for assessing the lesion; the site; any reti-
nal detachment and the type of exudate; signs of hemorrhage; choroidal, scleral,
or optic nerve infiltration; and pineal enlargement and impregnation)
• Cranial X-ray (it may identify areas of calcification that are pathognomonic for
RB)
• X-ray of the chest and skeleton (to check for any distant metastases)
• Liquor cytology (to rule out any meningeal dissemination)
• Bone marrow examination (to rule out any medullary involvement)
• Histological confirmation (it is unnecessary when ophthalmoscopic and radio-
logical findings suffice to confirm the diagnosis)
• PET/CT and skeletal scintigraphy (their use in RB is not standardized and rou-
tine yet. According to recent studies, PET/CT might be useful for staging and for
assessing response to neoadjuvant chemotherapy and final outcome in stage III
RB [93]. The routine use of preoperative bone scanning is not recommended, not
even in patients with locally advanced RB, and it should only be performed in
patients with documented extraocular metastatic disease ([4]))
The classification in stages historically used for RB was first proposed by Reese
and Ellsworth [32], but international efforts to adopt a uniform staging system led
to a new staging systems for RB, capable of covering the whole spectrum of the
disease [17, 61].
The differential diagnosis of RB should include parasitic lesions (toxocara
canis), retinal detachments, and granulomatous uveitis.
11.13.4 Pathology
Histologically, RB shows differing degrees of differentiation within the tumor,

ranging from undifferentiated anaplastic cells (retinoblasts) to better-differentiated
cells forming rosettes (Flexner–Wintersteiner rosettes).
228 M. Podda et al.
11.13.5 Treatment
RB should be diagnosed and treated at specialized centers with integrated expertise

in oncological ophthalmology, pediatric oncology, and radiotherapy. Current treat-
ment options for RB, alone or in combination, include:
1. Demolitive therapy (enucleation): It is nonetheless always essential to consider

the feasibility of a more conservative treatment, even in unilateral forms.
2. Conservative therapy, using the following treatments, alone or in combination:
• Systemic chemotherapy: For large tumors that cannot be treated with local
therapies alone, for relapsing tumors, and as an adjuvant to enucleation in
cases with high-risk histopathological characteristics. The chemotherapeutic
agents most commonly used are carboplatin, vincristine, and etoposide.
Cyclosporine has also been used to overcome drug resistance. Other drug
combinations have reportedly been used, such as a two-drug protocol with
vincristine and carboplatin, to contain the side effects of etoposide.
• Local chemotherapy: subconjunctival/subtenon route and superselective
intra-arterial chemotherapy.
• Transpupillary thermotherapy.
• Laser photocoagulation.
• Cryotherapy.
• Plaque brachytherapy.
• External beam radiotherapy: RB is highly radiosensitive and the retina is
fortunately relatively radioresistant.
11.14 Langerhans Cell Histiocytosis (LCH)
The incidence of LCH is 0.2–1/100,000 children per year. It may develop at any
age, from birth to adulthood, with a peak incidence between the first and third years
of life and a higher frequency in males (M/F = 2). The currently prevailing etiologi-
cal hypothesis is that this is a reactive rather than a neoplastic proliferation, second-
ary to an impaired immune regulation and characterized by an accumulation of
dendritic cells in various organs and tissues where they are normally found, i.e., the
skin (Langerhans cells), bone (osteoclasts), liver (Kupffer cells), brain (microglia),
blood (monocytes), lung (alveolar macrophages), spleen, thymus, lymph nodes,
connective tissue, and hematopoietic marrow.
LCH is traditionally divided into three groups depending on the number of lesions
and their distribution:
1. Unifocal eosinophilic granuloma, which is mainly osseous or pulmonary

2. Single-system multifocal, e.g., multifocal bone lesions:
In forms 1 and 2, the clinical condition may remain silent for a long time and
the diagnosis may be incidental at the time of X-rays performed for other reasons.
The most common symptom is pain involving the bone segment affected, and
sometimes there is swelling and functional impairment. The clinical signs depend
on the site: involvement of the orbital cavity may cause proptosis; lesions involving
the temporal bone may become apparent from a chronic otitis media or a mastoid
abscess; lesions involving the spine can develop with neurological impairments
(e.g., paraplegia), and mandibular lesions can be revealed by dental avulsions.
3. Multifocal multisystem:
– Abt–Letterer–Siwe disease: LCH including the abdominal viscera; it typi-
cally involves the bone, lung, skin, and lymph nodes, but any organ system
may be affected during the course of the disease. It is characterized by non-
specific symptoms such as fever, weight loss, irritability, and lethargy, asso-
ciated with adenopathies, hepatosplenomegaly, anemia, and sometimes
pancytopenia. Patients may have eczematous–seborrheic and papulo-
infiltrative skin lesions. The oral mucosa and gastrointestinal tract may be
involved (gingivostomatitis and enteritis), or there may be infiltration of the
external auditory canal (otalgia and otorrhea) or damage to the liver paren-
chyma (hypoprotidemia, ascites, and jaundice) or lungs (dyspnea, cyanosis,
cough, pneumothorax) and diffuse infiltration of the bone marrow. The
prognosis depends on which organs are involved (liver, spleen, hematopoi-
etic system) and on the response to treatment; it is generally poor.
– Hand–Schuller–Christian disease: multiple lithic lesions, diabetes insipidus,
and exophthalmos; this condition has a more favorable course.
11.14.3 Diagnosis and Staging
The staging investigations depend on the sites involved and may include:
• Plain radiographs and radioisotopic bone scans to identify bone lesions; their
radiological appearance may be pathognomonic (“mold” teca lesions, vertebra
plana) or may simulate benign lesions (dental cysts, osteomyelitis) or malignan-
cies (Ewing sarcoma).
• Brain MRI + gadolinium.
• Thin-slice chest CT scan: This is preferable to standard chest X-ray and should
be performed to rule out any parenchymal involvement.
• Abdominal US in cases of low clinical suspicion and abdominal CT scan
otherwise.
• PET: One of the most important issues in the management of LCH is how to
ascertain the extent of involvement and the disease’s activity (vs. quiescence) in
any particular organ so that appropriate therapy can be instituted. According to a
few studies, PET is better than bone scans or plain radiographs for identifying all
active lesions, distinguishing them from healed lesions, and demonstrating a nor-
230 M. Podda et al.
malized uptake in a lesion treated earlier. FDG-PEt also seems to be more sensi-
tive than either MRI or bone scanning in detecting osseous abnormalities in
LCH. Finally, PET might be useful for assessing response to therapy. A greater
or lesser disease activity is reflected by changes in the SUV, which become evi-
dent earlier than in plain films or bone scans. PET may be helpful for assessing
all bone lesions except those in the spine, where MRI is superior. PET may also
help to measure response in the spleen because splenomegaly may persist, while
a decrease in FDG uptake may suggest inactive disease [89]. At the present time,
the routine use of FDG-PET for diagnosing, assessing response, and following
up LCH patients is not recommended; it is only used in selected cases.
• Biopsy/curettage: Histological diagnosis is mandatory; sometimes biopsy and
curettage are curative alone.
11.14.4 Pathology
The term “histiocytosis” describes a heterogeneous group of diseases of the reticu-

loendothelial system sharing the same pathological picture, which is characterized
by the infiltration in the tissues and proliferation of cells belonging to the mono-
cyte–macrophage system. A definitive diagnosis is established either from positiv-
ity on staining with anti-CD1a antibody on frozen sections or from the finding of
Birbeck granules on electron microscopy.
11.14.5 Therapy
Monostotic LCH: This may heal spontaneously or after curettage or biopsy alone.
Systemic treatment is reserved for locally extensive lesions at risk of fracture,
associated with functional limitations and pain and with disease at particular
sites, such as the vertebrae (in the event of bone marrow compression), or with
craniofacial involvement with an intracranial component.
Polyostotic LCH: Skeletal lesion may regress spontaneously (prompting a wait-and-
see strategy) or respond to minimal treatment, but they can also recur several times.
Chemotherapy is indicated for the polyostotic form, for which a combination of
prednisone and vinblastine for 12 months is currently considered the standard.
Multisystem LCH: Treatment for this form is currently controversial. The drugs
generally used include prednisone, vinblastine, 6-mercaptopurine, and metho-
trexate. Radiotherapy is reserved for extremely selected cases.
11.15 Hepatoblastoma (HB) [58]
HB is the most common malignant liver tumor in the pediatric population, account-
ing for over 65 % of all liver cancers diagnosed in children under 15 years old. Its
annual incidence is 0.05–0.15/100,000 under 15 years of age. It is diagnosed mainly

in children under the age of 5, at a median age of 18 months, with a slight predomi-
nance in white males and in association with premature birth and low/very low birth
weight. An increased risk of HB has been reported in children with Beckwith–
Wiedemann syndrome, familial adenomatous polyposis syndrome, and trisomy 18.
Other risk factors include infertility treatments, preeclampsia, high maternal pre-
pregnancy weight, olygohydramnios/polyhydramnios, parental tobacco use, and
parental occupational exposure to metals.
• Abdominal mass.
• Anorexia, failure to thrive, abdominal pain, and abdominal distension.
• Jaundice is rarely seen in HB, while it is more common in biliary rhabdomyosar-
coma and undifferentiated sarcoma of the liver.
• Thrombocytosis is typical of an HB, due to a paraneoplastic effect related to the
tumor’s production of interleukin-6, a potent growth factor for megakaryocytes.
• αFP measurement: This is a reliable predictor of outcome and may also be used
to identify poor response to treatment and relapsing or metastatic disease. High
αFP levels may also be seen in infants with yolk-sac tumors, sarcomas, and
hamartomas.
• Abdominal Doppler US: This is the first imaging modality to be used in infants
suspected of having a liver tumor.
• Contrast-enhanced CT of the lungs and abdomen and abdominal MRI: These
tests provide the best view of the tumor’s vascular anatomy and more precise
picture of its margins. Angio-MRI may be useful in cases of vascular involve-
ment. Staging currently uses the pretreatment extent of disease (PRETEXT) sys-
tem and a reassessment after neoadjuvant chemotherapy (posttreatment extent of
disease, POSTTEXT), for which CT and MRI are mandatory. CT also enables an
assessment of any lung metastases.
• DWI and MRI with gadoxetate disodium may enable a preoperative assessment
of the extent of the disease, but they are not used routinely and their results need
to be interpreted with care.
• In the literature, there is no clear evidence of the role of FDG-PET in hepatoblas-
toma. The few studies available show discordant results [40].
• Biopsy: To ensure optimal treatment, it is currently recommended that all patients
with a liver mass undergo a biopsy. In the European SIOPEL protocol, a tumor
biopsy is required to confirm diagnosis before starting chemotherapy, and it does
not upstage a patient if a subsequent complete resection is performed. The
American COG protocol allows for primary tumor resection without a biopsy if
this seems feasible.
232 M. Podda et al.
11.15.4 Pathology
HB is an embryonal tumor that generally presents with two main histological types:
epithelial (in 56–67 % of cases) and mixed (epithelial and mesenchymal). The epi-
thelial variants are further divided into pure fetal (31 %, with a better prognosis),
embryonal (19 %), macrotrabecular (3 %), and small-cell undifferentiated (3 %,
with the worst prognosis).
11.15.5 Treatment
Surgical resection is the mainstay of curative therapy, but only one in three to one in
two patients newly diagnosed with HB will have resectable disease at the time of
their diagnosis. Cisplatin remains the core chemotherapeutic agent, as recognized
by all the main liver study groups and used in all protocols, possibly associated with
doxorubicin. Neoadjuvant cisplatin-based chemotherapy has improved the survival
of patients with initially unresectable HB by increasing the number of patients
whose tumors can be resected. Chemotherapy is not indicated in cases with a pure
fetal histology because surgical resection alone is curative. Patients whose tumor
may not be resectable even after neoadjuvant chemotherapy should be referred to a
liver transplant center.
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Lymphoma
12
Egesta Lopci and Arnoldo Piccardo
Contents
12.1 Hodgkin Disease ........................................................................................................... 239
12.1.1 Staging HD ...................................................................................................... 241
12.1.2 Treatment Response and Follow-Up ............................................................... 242
12.2 Non-Hodgkin Lymphoma ............................................................................................. 245
12.2.1 Staging ............................................................................................................. 245
12.2.2 Treatment Response and Follow-Up ............................................................... 247
12.3 Technical Aspects.......................................................................................................... 248
12.3.1 Timing of FDG Imaging Related to Chemotherapy ........................................ 248
12.3.2 Patient Preparation .......................................................................................... 249
12.3.3 Tracer Injection ............................................................................................... 249
12.3.4 PET/CT Acquisition ........................................................................................ 250
12.4 Take-Home Messages ................................................................................................... 250
References ................................................................................................................................ 251
12.1 Hodgkin Disease
In pediatric population, approximately 12 % of all malignancies are represented by

lymphoma, and of these 40 % are composed of Hodgkin disease (HD) [1]. The peak
incidence is around 14 years of age, thus representing frequently an adolescent or
youngster malignancy [2]. The majority of patients affected by HD have an initial
disease presentation with painless supraclavicular or cervical adenopathies. Also ante-
rior mediastinum involvement is present, especially in adolescents and young adults
[3]. B symptoms (unexplained fever, night sweats, and weight loss) are documented
in 26–38 % of childhood HD and along with bulky masses (>10 cm in maximum
diameter on CT) are still considered as unfavorable prognostic factors in HD [4].
E. Lopci, MD (*)
Nuclear Medicine Department, Humanitas Clinical and Research Center,
Via Manzoni, 56-20089, Rozzano (Milano), Italy
e-mail: egesta.lopci@cancercenter.humanitas.it; egesta.lopci@gmail.com
A. Piccardo, MD
Nuclear Medicine, Galliera Hospital, Genoa, Italy

DOI 10.1007/978-3-319-21371-2_12
240 E. Lopci and A. Piccardo
From a pathological point of view, HD is characterized by multinucleated giant

cells, so-called Reed-Sternberg cells, or other mononuclear variants that arise from
germinal center B cells, interspersed in a prevailing background of inflammatory
environment [4]. HD can be associated with Epstein-Barr virus infection and immu-
nosuppression, although this later one seems to be less frequent than in pediatric
NHL. According to the World Health Organization (WHO) classification, HD can
be divided into the classical form, which is the most representative one, and the
nodular lymphocyte predominant type (~10 %). Classical HD is furthermore divided
into four subtypes that, according to their incidence, can be listed as follows: (1)
nodular sclerosing (up to 80 %), (2) mixed cellularity (variable from 15 to 45 %),
(3) lymphocyte rich (1–3 %), and (4) lymphocyte depleted (1–3 %) [5, 6].
The staging system most widely used for pediatric HD is based on the Ann Arbor
classification [7], later on adapted to the Cotswolds modification that contemplates also
bulky disease [8] (Table 12.1). Nowadays however, the management of pediatric HD
relies not only on the disease stage but rather on the risk stratification of the patients.
These risk factors, as mentioned in some of the ongoing trials, can comprise B symp-
toms, mediastinal and peripheral lymph node bulk, extranodal extension of disease to
contiguous structures, number of involved nodal regions, Ann Arbor stage, serum
markers of inflammation, gender, as well as response to initial chemotherapy [3, 4].
In general HD patients show an overall good prognosis, especially in case of
limited-stage disease and absence of unfavorable factors, with a 5-year event-free
survival superior to 98 %. More advanced forms and high-risk patients still benefit
by the combination of multiagent chemotherapy regimens and radiotherapy, being
HD a highly chemo- and radiosensitive disease [5]. The nodular lymphocyte pre-
dominant type tends to be more indolent than the classical form, with a propensity
for multiple late relapses and risk for transformation into diffuse large B cell lym-
phoma (DLBCL) [4]. Anyhow, the overall prognosis of this HD subtype remains
favorable [10]. Thus, the excellent results yielded so far have led to the necessity for
new therapeutic protocols, focusing on the optimization and reduction in treatment-
related sequelae in early-stage disease and improvement in survival rate in patients
with advanced-stage disease and unfavorable risk stratification.
Table 12.1 The Ann Arbor staging system [7, 9]

Stage I Involvement of a single lymphatic site (I) or a single extralymphatic organ (IE)
Stage Involvement of two or more lymph node regions (II) or localized involvement of a
II single extralymphatic site in association with regional lymph node involvement on the
same side of the diaphragm (IIE)
Stage Involvement of lymph node on both sides of the diaphragm (III), with extralymphatic
III involvement (IIIE) or with involvement of the spleen (IIIS) or both (IIIE, S)
Stage Diffused or disseminated involvement of lymphatic or extralymphatic organs
IV including any involvement of the liver or bone marrow, lungs (other than by direct
extension from another site), or cerebrospinal fluid
B symptoms = Fever (temperature >38 °C), drenching night sweats, unexplained loss of >10 % of
body weight within the preceding 6 months; E = Involvement of a single extranodal site that is
contiguous or proximal to the known nodal site; S = Splenic involvement
12 Lymphoma 241
In this context, instrumental imaging becomes crucial either for disease staging
or for a proper treatment response assessment. This fact is confirmed by the intro-
duction of early response to chemotherapy as a predictor to disease outcome in the
Children’s Oncology Group (COG) studies [3, 4].
12.1.1 Staging HD
18F-FDG PET has been increasingly incorporated into the diagnostic and therapeu-
tic work-flow of many pediatric malignancies. This imaging modality allows an
earlier identification of primary tumors as well as their metastatic spread, thus sig-
nificantly improving treatment planning and overall survival. In particular, 18F-
FDG PET is a well-established modality for the initial assessment of adult and
pediatric HD. As a noninvasive imaging technique, it allows for a whole-body
detection of all lymphatic and extralymphatic sites of disease. At initial staging
18F-FDG PET/CT shows a sensitivity, specificity, and accuracy of 96.5 %, 100 %,
and 96.7 %, respectively, markedly superior to conventional imaging, including
computed tomography (CT) [11–13]. This performance is maintained throughout
the entire range of histological subtypes of HD that are in general characterized by
a high avidity for the tracer [14]. The use of morphological imaging such as CT or
even MRI should be anyhow considered in the initial evaluation of HD patients in
case of unusual extralymphatic involvement or when bulky masses are detected, in
order to better define structural infiltration and plan consolidation radiotherapy.
In HD staging, a crucial site of disease localization is represented by bone/bone
marrow. Although the rate of bone marrow involvement is not as high as in adult
population, still there is an incidence of 4–6.5 % in more advanced HD stages in
pediatric population [15, 16]. Traditionally, bone marrow biopsy (BMB) at the level
of the iliac crests was considered as gold standard and should still be performed in
case no advanced imaging with PET is available prior to treatment start. Nowadays,
the results obtained by 18F-FDG PET/CT in defining bone marrow involvement
guarantee a better detection of HD extent and overcome completely the necessity to
perform a BMB in case of positive findings [5, 17]. The patterns of bone marrow
involvement are variegate and comprise either a multifocal pattern, with three to
more lesions located in the axial skeleton or proximal limbs, single foci of 18F-
FDG uptake, or diffused heterogeneous uptake with sites of more intense focal
involvement [15, 17]. This later pattern should not be confused with the homoge-
nously increased bone marrow activation present in advanced HD cases and consis-
tent with systemic/paraneoplastic symptoms [15]. Recent recommendations in adult
lymphoma imaging also support the superior performance of 18F-FDG PET/CT in
bone marrow assessment either at an early stage, when the risk of bone marrow
infiltration is very low, or in advanced HD, given the high positive predictive value
of the modality [18].
As a consequence of the better assessment of HD, 18F-FDG PET/CT determines
a significant impact in patient treatment, either by upstaging or downstaging the
disease. The percentage of change varies from 9 to 50 % of the cases, but by
summarizing the results from different papers [19–25], the cumulative change can
be estimated around 20 %.
12.1.2 Treatment Response and Follow-Up
Posttreatment evaluation with 18F-FDG PET/CT is known to be significantly cor-

related with patient outcome [26]. Its proper application during the course of treat-
ment or after completion of chemotherapy can help identify patients who could
benefit from additional therapy and avoid unnecessary treatment in patients with a
low risk of relapse and a complete metabolic response [27]. In clinical practice the
imaging response, including qualitative criteria such as the metabolic response to
treatment, is used as a surrogate for patient outcome [28]. In limited-stage HD, the
PET evaluation at the end of treatment has been reported to be highly predictive of
PFS and overall survival [29]. Also in advanced-stage HD, consolidation radio-
therapy can be safely omitted in PET-negative patients after completion of chemo-
therapy. In response assessment, a negative 18F-FDG PET after chemotherapy
anticipates an excellent prognosis in contrast to a positive scan where the risk of
disease recurrence increases significantly [21, 30]. No significantly increased risk of
early relapse or progression has been reported in these patients even in those with
residual masses on CT, but metabolically silent on 18F-FDG PET [31]. The above-
mentioned results have led to the new recommendations for the assessment of lym-
phoma, also known as the Lugano classification [18]. For response assessment in
FDG-avid lymphoma, the criteria suggested are based on the 5-point scale (Deauville
score) [32], both for clinical practice and research trials including interim and end-
treatment evaluation.
In pediatric population response assessment can be obtained either after two
cycles of chemotherapy, thus defining the early response, or at the end of treatment
(Figs. 12.1, 12.2 and 12.3). In the first case the information is regarded as crucial for
the planning, and in different multicenter protocols, the achievement of a complete
metabolic response early in time could safely lead to reduction in chemotherapy
exposure and/or the omission of radiotherapy [33, 34]. In other cases, response-
adapted therapy from the Children’s Cancer Group (CCG) followed a gender-tai-
lored consolidation protocol in advanced HD based on early response on PET [35].
As for response criteria in pediatric HD, no universally accepted criteria have
been reported. However, many attempts have been done, either by applying the
International Harmonization criteria for assessment of FDG PET response or by
investigating the 5-point scale [5, 36, 37]. An alternative method to define meta-
bolic response on PET has been proposed by the study group of the EuroNet-
PHL-C1 trial (EudraCT 2006-000995-33), after dedicated evaluation of 898
patients [38]. The method gives a quantitative analysis (qPET) computed as an
extension of the Deauville scale, resulting more consistent with the continuum in
metabolic response observed in reality. This quantification however requires dedi-
cated software, and upon the availability of the nuclear medicine center, qPET can
12 Lymphoma 243
a b d
Fig. 12.1 A 12-year-old female affected by Hodgkin’s lymphoma. PET/CT scan on initial staging
showed a big lymph-node cluster characterized by intense FDG uptake in the right supraclavicular
region (a and c). Repeated study was done after a 2 cycles of chemotherapy (b and d), which
showed complete metabolic response to therapy
a b
d
Fig. 12.2 A 11-year-old male affected by Hodgkin’s lymphoma. PET/CT scan on initial staging
showed a left lung localization of disease characterized by intense FDG uptake (a and c). Repeated
study was done after a 2 cycles of chemotherapy (b and d), which showed an incomplete metabolic
response to therapy
be used as a reliable method for early response assessment in pediatric

HD. Otherwise, as for adult lymphoma, the 5-point scale suggested by the Lugano
classification is recommended [18].
a b f
d h
c
Fig. 12.3 This is a 17-year-old male affected by Hodgkin’s lymphoma. PET/CT scan on initial
staging showed increased FDG uptake in a large right mediastinal mass and in laterocervical
lymph-nodes. (a and e). Repeated study was done after a 2 cycles of chemotherapy, which showed
an incomplete metabolic and morphological response to therapy (b and f). At the end of treatment,
PET/CT scan showed a complete metabolic response to therapy (c and g). Six months later, PET/
CT showed a mediastinal recurrence of disease (d and h)
At the end of chemotherapy, 18F-FDG PET is carried out to determine the need
for consolidative radiation therapy and is reported a have a very high and indepen-
dent prognostic role [3, 26]. Especially in case of positive findings after two cycles
of chemotherapy, the use of end-treatment PET is almost mandatory. What is con-
sidered to be very high at this point in time is the negative predictive value of the
method, whereas the positive predictive value is reported rather variable and can
lead to false-positive findings [39]. Therefore, the proper timing for the scanning is
defined by the day of the last cycles of chemotherapy and should be comprised
between 3 and 4 weeks after the completion of therapy [36].
12 Lymphoma 245
No consolidated use of 18F-FDG PET/CT exists in the follow-up of pediatric

HD, unless end-treatment evaluation shows equivocal findings or noncomplete met-
abolic response. On counterpart, the integration of PET/CT into radiation treatment
planning is advised because of the substantial impact it can have on treatment vol-
umes within the target definition by reducing the risk of acute radiation-induced
toxicity and potentially lowering the rate of long-term sequelae, including second-
ary malignancies [40].
12.2 Non-Hodgkin Lymphoma
Non-Hodgkin lymphoma (NHL) accounts for 60 % of childhood lymphomas and

represents about 7.5 % of pediatric cancer; it is rare in infants and has its peak inci-
dence at the age of 7 years [1]. NHL includes a large and very heterogeneous group
of systemic malignancies but in childhood and adolescence is an aggressive sys-
temic disease characterized by mature B cell immunophenotype. In particular most
pediatric NHL cases belong to one of four categories: Burkitt lymphoma and B cell
acute lymphoblastic leukemia (40–50 % of cases), followed by lymphoblastic lym-
phoma (20–25 %), anaplastic large-cell lymphoma (10–15 %), and diffuse large B
cell lymphoma (10 %) [41, 42]. In addition, unlike in Hodgkin lymphoma with only
few tumor cells, NHL consists of about 85–99 % of highly proliferative neoplastic
cells (Fig. 12.4).
Burkitt lymphoma is an aggressive and rapidly proliferating tumor and doubles
within 12–48 h [43, 44], and it often leads to gastrointestinal and urogenital
obstructions.
The most common localization of lymphoblastic lymphomas is the mediastinum
(large mediastinal mass) followed by the spleen, bone marrow, central nervous sys-
tem, and peripheral lymph nodes [45].
Anaplastic large-cell lymphomas are characterized by peripheral adenopathy but
often show extranodal involvement such as the skin, soft tissues, lungs, and cortical
bone [45, 46]. Most children affected by anaplastic large-cell lymphomas carry the
ALK-gene translocation. The prognosis of ALK+ patients is better than that of
ALK− [47].
Diffuse large B cell lymphoma (DLBCL) is rare in pediatric patients. However,
it is the most common lymphoma subtype in patients with congenital, iatrogenic,
or acquired immunodeficiency. DLBCL is often characterized by nodal and
extranodal localizations, but a solely gastrointestinal presentation is not
uncommon.
12.2.1 Staging
The staging system in childhood NHL is defined according to the Murphy (St. Jude)
criteria (Table 12.2) [48]. At this time, it seems to be important to consider that the
bone marrow infiltration in NHL is frequent (30–50 %) compared to Hodgkin lym-
phoma [15, 49]. Moreover considering that NHL aggressive behavior is the most
Fig. 12.4 This patient was a 16-year-old male who had Non-Hodgkin’s lymphoma. PET/CT scan
on initial staging showed multiple areas of increased FDG uptake in the spine and sacrum, but no
abnormal findings on the corresponding CT images
prevalent type found in children, the limited 18F-FDG PET and PET/CT sensitivity
in low-grade NHL is not relevant in this age group.
In this setting 18F-FDG-avidity was reported to be 100 % in Burkitt lymphoma
(18/18), 100 % in anaplastic large-cell lymphoma (14/14), 100 % in lymphoblastic
lymphoma (6/6), and 97 % in diffuse large B cell lymphoma (216/222) [14]. Overall,
PET/CT may show more nodal and extranodal lesions in patients with lymphomas
12 Lymphoma 247
Table 12.2 St. Jude/Murphy’s pediatric NHL staging system [47, 48]
Stage I A single tumor localization (nodal or extranodal) on one side of the diaphragm with
the exclusion of the mediastinum and abdomen
Stage II Two or more nodal or extranodal localizations on one side of the diaphragm
Stage III With nodal/extranodal involvement of both sides of the diaphragm or primary
intrathoracic or intra-abdominal tumors
Stage IV Any of the above with initial of the central nervous system, bone marrow, or both
when compared with contrast CT [50] and consequently may change disease stage
[22]. London et al. found that PET/CT performed better than conventional imaging
in the detection of malignant lesions with significantly improved sensitivity (95.6 %
vs. 70.1 %) [12].
In particular 18F-FDG PET seems to be more effective in anaplastic large-cell
lymphomas, diffuse large B cell lymphomas, and Burkitt lymphoma when extrano-
dal involvement is frequent [51, 52]. In this field the spleen involvement may be
easily recognized by using 18F-FDG PET or PET/CT [53].
However, some physiological tracer uptakes can affect 18F-FDG PET/CT sensi-
tivity at the time of first staging in children. In particular in NHL organs with high
physiological uptake such as brain or kidneys might be primarily involved [45].
Moreover, lymphoblastic lymphoma is often associated with diffuse bone marrow
infiltration. Consequently, the differentiation between generalized bone marrow
activation from bone marrow infiltration can be sometimes impossible, thus false-
positive or false-negative 18F-FDG PET/CT results can be reported [49].
12.2.2 Treatment Response and Follow-Up
In non-Hodgkin entities, tumor masses consist of more than 85 % tumor cells. In

contrast to Hodgkin lymphoma, the reduction of the FDG uptake under chemo-
therapy in non-Hodgkin disease mainly reflects the reduction of the number of liv-
ing tumor cells [54]. However, because of the limited resolution of PET scanners
(about 0.4 cm with modern detector systems), eradication of tumor cells cannot be
assumed if 18F-FDG PET is negative during or at the end of treatment [55].
Therefore, evaluation of chemosensitivity early in the course of chemotherapy
might be of higher predictive value than at the end of treatment [5].
Children and adolescents with non-Hodgkin lymphoma are usually treated with
chemotherapy and without radiotherapy, therefore late effects caused by radiation
exposure are not a matter of consideration as they are in Hodgkin lymphoma [5].
However, the risk of inadequate response to chemotherapy might be higher than in
Hodgkin lymphoma. The main challenge therefore is to differentiate good respond-
ers with a high probability to be cured from poor responders who require treatment
intensification.
Reduction of chemotherapy to avoid late effects in very good responders might
be relevant in well-defined subpopulations.
On the other hand, considering the data recently reported in NHL adults patients,
the positive predictive value (PPV) of interim PET seems to be not very high [56, 57].
Thus, negative 18F-FDG PET/CT scan may predict adequate response, but positive
results do not justify treatment intensification.
In this field improvement of response criteria to increase the prognostic value of
PET is crucial. Some authors [56] performed additional semiquantitative analyses
of interim PET scan, and they found that a reduction of maximum standardized
uptake value (Δ SUV max) by >70 % is related to a significantly better progression-
free survival and overall survival rates.
More in general, for adults with NHL, results concerning interim 18F-FDG PET
are heterogeneous. Negative predictive value (NPV) depends on the histological
subtype. It is high in diffuse large B cell lymphoma and therefore suggests excellent
prognosis. In contrast, NPV in anaplastic large-cell lymphoma is variable in correla-
tion to ALK status (high in ALK+) [17]. Semiquantitative methods or even biopsy
of PET-positive sites seems to improve the PPV of interim 18F-FDG PET in diffuse
large B cell lymphoma [57].
Prospective trials are being planned to understand the role of interim 18F-FDG
PET in pediatric non-Hodgkin lymphomas. However, some authors [58, 59],
investigating a small number of patients, reported high negative predictive value
of 18F-FDG PET after two courses of chemotherapy because none of the patients
with negative interim 18F-FDG PET relapsed after the end of therapy. On the
other hand, it was reported [12] a high specificity level (99.2 %) for 18F-FDG
PET/CT as a predictor of poor treatment response in children with non-Hodgkin
lymphoma.
However, the role of interim PET/CT in pediatric NHL is not fully clarified. In
this field the prognostic role of a negative interim PET and PET/CT has been ques-
tioned [19, 60], and more recently Bakhshi et al. [61] did not find any correlation
between interim PET/CT findings and outcome in pediatric NHL.
When taking into account the role of 18F-FDG PET at the end of the treat-
ment, a high NPV in patients affected by Burkitt lymphoma was reported [62]. In
this field no patient with negative 18F-FDG PET relapsed or turned 18F-FDG
PET positive on surveillance. On the contrary when the positive 18F-FDG PET
results at the end of treatment have been compared with histopathological find-
ings after biopsy, Riad et al. [63] reported a very low 18F-FDG PET PPV (25 %).
Therefore, the authors recommended biopsy if 18F-FDG PET is positive at the
end of treatment [5].
More in general 18F-FDG PET and PET/CT have an important role in
assessing lymphomas status during follow-up after the end of therapy [64]. In
these cases the sensitivity and specificity were reported to be 90 % and 88 %,
respectively [59].
12.3 Technical Aspects
12.3.1 Timing of FDG Imaging Related to Chemotherapy
It is suggested that 18F-FDG PET/CT should be performed immediately before the first
course of chemotherapy and more in general immediately before a new course [65].
12 Lymphoma 249
Table 12.3 Summary of main aspect to consider for 18F-FDG PET/CT imaging in pediatric
lymphoma
Timing of PET/CT Patient preparation Tracer injection PET/CT acquisition
Immediately before Avoid strenuous Minimum PET images in 3D mode
the first course of exercise injected activity covering at least from
chemotherapy of 26 MBq the upper neck to the
upper thighs
Immediately before a Fast for at least 4–6 h 3 MBq/kg in 3D CT component: dose
new course of Preferred blood glucose mode modulation method able
chemotherapy levels below 120 mg/dl to reduce radiation
exposure
FDG uptake during the first days of a course of chemotherapy may underesti-
mate the disease extension at the time of first staging and the amount of viable dis-
ease after the courses of the chemotherapy (Table 12.3).
A full explanation of the scan should be given to the patient and parents.
The need for sedation or anesthesia should be identified in advance, and an expe-
rienced anesthetist should be involved.
The patient should avoid strenuous exercise the day before the exam to avoid high
tracer uptake in skeletal muscle [66]. The child should fast for at least 4–6 h before
the study but should drink water to maintain good hydration. The blood glucose level
should be assessed, and the preferred fasting blood glucose is below 120 mg/dl [66].
To reduce stress for the child before tracer injection, i.v. access should be ideally
obtained outside the nuclear medicine department.
To reduce tracer uptake in brown fat, a warm blanket may be of help. In this field some
premedications have been suggested such as a moderate dose of oral diazepam, oral pro-
pranolol (1 mg/kg, max. 40 mg 60–90 min before administration of FDG) for children of
10 years and older [67, 68], and intravenous fentanyl (0.75–1.0 mcg/kg) [69].
12.3.3 Tracer Injection
If a central line is used for tracer injection due to difficult i.v. access, the line should
be flushed with at least 20 ml of 0.9 % normal saline solution.
The injected activity of FDG depends on the patient’s weight and the type of
acquisition (2D or 3D). Acquisition in 3D mode is preferable due to its higher sen-
sitivity. A minimum injected activity of 26 MBq has been introduced, and more in
general the last version of EANM dosage card suggests injected activity according
to body weight and mode scanning acquisition (2D or 3D) [70]. However, it is rec-
ognized that other ways of calculating the injected activity of FDG in children are
possible (i.e., 6 MBq/kg body weight FDG in 2D mode scanning acquisition and
3 MBq/kg in 3D mode) [71].
The patient should rest until the start of PET scanning. Scan acquisition should
start 1 h after tracer injection. Before the acquisition, the child should be encour-
aged to void.
12.3.4 PET/CT Acquisition
To avoid movement artifacts and to ensure the right positioning, all children should
be comfortably immobilized during study acquisition.
The extent of the acquisition depends on the indication. For example, in the fol-
low-up 18F-FDG PET/CT scans in patients with lymphoma and no bone or bone
marrow involvement, it may suffice to image from the base of the skull to the upper
thighs. On the other hand in lymphoma patients with suspected bone or bone mar-
row disease, the entire legs and arms should be included [66].
Acquisition parameters depend largely on the detector and the type of scanner
used; however, we suggest to acquire PET images in 3D mode from the upper neck
to the upper thighs, by means of sequential fields of view, each covering 12 cm
(matrix of 256 × 256), over an acquisition time of 3 min of acquisition time for bed
position.
CT component of PET/CT should be used for attenuation correction and ana-
tomical localization of PET findings. To minimize dose exposure, we suggest to use
the dose modulation method to be able to adjust the mA to the thickness of the
patient and significantly reduce radiation exposure (about 25–35 %) without a
reduction in image quality [72]. The CT scan may be acquired during mild expira-
tion to obtain the best alignment of the diaphragm [73].
12.4 Take-Home Messages
• 18F-FDG PET/CT is the modality of choice for the initial staging of pediatric
HD and the majority of NHL patients. In case of undetectable lymphoma on
PET, conventional imaging with CT should be considered and maintained
throughout the entire diagnostic and therapeutic workup.
• Bone marrow biopsy can be safely omitted in case a 18F-FDG PET is performed
for HD patients but should still be considered in advanced NHL in case of nega-
tive PET findings.
• Response assessment in pediatric HD can be obtained immediately after the sec-
ond cycle of chemotherapy and must be repeated at the end of treatment in case
of positive findings. Response criteria can be based on visual (Deauville score)
or quantitative parameters (qPET) based on the software availability of the
nuclear medicine center. So far, only in clinical trials PET-based response after
two cycles can be used to adapt patient treatment.
• In NHL response, assessment should still be based on combined morphological
and metabolic criteria.
12 Lymphoma 251
• No consolidated use of 18F-FDG PET/CT in the follow-up of pediatric lym-

phoma. The method might be used only in case of equivocal findings at the end-
treatment evaluation or for monitoring a non complete metabolic response.
• 18F-FDG PET/CT evaluation is necessary for the optimization of RT planning in
both HD and NHL.
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Neuroblastoma
13
Vittoria Rufini, Maria Vittoria Mattoli,
and Maria Carmen Garganese
Contents
13.1 Introduction to the Clinical Context 256
13.2 Available Diagnostic Tools in Neuroblastoma 258
13.3 MIBG Scintigraphy: Technical Aspects 258
13.3.1 Radiopharmaceutical 258
13.3.2 Preparation and Interference ......................................................................... 259
13.3.3 Administered Activity ................................................................................... 260
13.3.4 Instrument Specifications .............................................................................. 260
13.3.5 Imaging Procedure 260
13.4 MIBG Scintigraphy: Clinical Information 261
13.4.1 Principal Information, Pitfalls, Limitations .................................................. 261
13.4.2 Added Value and Clinical Indications........................................................... 263
13.4.3 Criteria for Evaluation of Disease Extent 266
13.5 PET Radiopharmaceuticals for NB 266
13.6 Available Therapeutic Tools in Neuroblastoma 269
13.7 131I-MIBG Therapy: Technical Aspects 270
13.7.1 Radiopharmaceutical..................................................................................... 270
13.7.2 Therapeutic Procedure 270
13.8 131I-MIBG Therapy: Clinical Application 271
13.8.1 MIBG as Monotherapy in Resistant/Recurrent Disease ............................... 271
13.8.2 MIBG as Front-Line Therapy ....................................................................... 271
13.8.3 MIBG in Combination with Other Therapies ............................................... 271
13.8.4 Side Effects 272
Suggested Literature 273
V. Rufini (*) • M.V. Mattoli

Department of Radiological Science, Institute of Nuclear Medicine,
Università Cattolica del Sacro Cuore,
Largo a. Gemelli, 8, Rome 00168, Italy
e-mail: v.rufini@rm.unicatt.it
M.C. Garganese
Nuclear Medicine Unit, Department of Imaging,
Piazza S. Onofrio 4, Rome 00165, Italy

DOI 10.1007/978-3-319-21371-2_13
256 V. Rufini et al.
13.1 Introduction to the Clinical Context
Neuroblastoma (NB) is the most common extracranial malignant solid tumour in

children, accounting for 8–10 % of all childhood neoplasms. The median age at
diagnosis is about 16 months [1, 2]. NB is derived from primordial neural crest
cells that normally differentiate into the sympathetic nervous system. The most
common site of primary tumour is the abdomen, mainly the adrenal gland (48 %),
although this tumour may arise from any site along the sympathetic nervous sys-
tem from the neck to the pelvis. About 50 % of patients have metastatic disease at
presentation, with a propensity to involve the bone marrow and cortical bone; also
lymph node and hepatic metastases are commonly seen, while lung and central
nervous system metastases are rare and usually associated with very poor out-
come [3, 4]. Related to their origin from the sympathetic nervous system, most of
these tumours are associated with high urinary levels of catecholamine metabo-
lites, such as vanillylmandelic acid (VMA) produced from norepinephrine,
homovanillic acid (HVA) formed from dopamine or dopamine. Occasionally the
tumour may cause hypertension.
NB is a complex and heterogeneous disease in terms of biology, clinical presen-
tation and behaviour, with different patterns from patient to patient. Indeed, some
tumours show spontaneous regression or show differentiation into benign ganglio-
neuroma, while others undergo progressive disease, usually fatal despite multi-
modal intensive therapies. Treatment protocols are stratified according to risk,
which is defined on the basis of biologic prognostic factors, such a histopathology,
chromosomal abnormalities and status of the MYCN oncogene, combined with
clinical prognostic factors, mainly age and clinical stage at presentation.
The International Neuroblastoma Staging System (INSS), developed in 1988 [5]
and modified in 1993 [6], is based on the extent of surgical tumour excision
(Table 13.1). In 2009, the International Neuroblastoma Risk Group (INRG) Task
Force developed the International Neuroblastoma Risk Group Staging System
(INRGSS), a new staging system designed for tumour staging before surgery and any
other treatment; this system is based on imaging findings instead of surgical-
pathologic data (Table 13.2) [7]. On the basis of the presence of one or more image-
defined risk factors (IDRFs), the new INRG Staging System defines two different
stages of localized disease (L1: no IDRFs; L2: one or more IDRFs) and one distant
metastatic disease (stage M). Stage MS (stage 4S of INSS) is a special category with
favourable prognosis, including infants less than 18 months of age, with metastases
confined to the liver, skin and/or bone marrow (if less than 10 % of all nucleated cells
in the culture smears or biopsy samples) [7]. Indeed, the INRGSS is meant to be used
in conjunction with, but not replace, the INSS [3].
For an accurate evaluation of disease extent, multiple tests are required both at
diagnosis and during follow-up, including bone marrow biopsy and urine catechol-
amine levels as well as anatomic and functional imaging modalities [3, 8].
Metaiodobenzylguanidine (MIBG) structurally resembles the adrenergic neu-
rotransmitter norepinephrine and is taken up by the human norepinephrine trans-
porter (hNET) in the cell membrane of sympathomedullary tissues and is stored into
the catecholamine-storing granules and adrenergic nerve endings by the vesicular
13 Neuroblastoma 257
Table 13.1 Summary of the International Neuroblastoma Staging System (INSS) tumour stages
Tumour
stage Description
1 Localized tumour with complete gross excision, with or without microscopic
residual disease; representative ipsilateral lymph nodes negative for tumour
microscopically. Nodes attached to and removed with the primary tumour may be
positive
2A Localized tumour with incomplete gross excision; representative ipsilateral
nonadherent lymph nodes negative for tumour microscopically
2B Localized tumour with or without complete gross excision, with ipsilateral
nonadherent lymph nodes positive for tumour; enlarged contralateral lymph nodes
negative microscopically
3 Unresectable unilateral tumour infiltrating across the midline (beyond the opposite
side of the vertebral column) with or without regional lymph node involvement, or
midline tumour with bilateral extension via infiltration (unresectable) or lymph
node involvement
4 Any primary tumour with dissemination to distant the lymph nodes, bone, bone
marrow, liver, skin and/or other organs (except as defined for stage 4S disease)
4s Localized primary tumour (as defined for stage 1, 2A or 2B disease) with
dissemination limited to the skin, liver and/or bone marrow (limited to infants
younger than 1 year, marrow involvement of less 10 % of total nucleated cells and
MIBG scan findings negative in the marrow)
Source: Brisse et al. [3]
Table 13.2 Summary of the International Neuroblastoma Risk Group Staging System (INRGSS)
Tumour
stage Description
L1 Localized tumour not involving vital structures, as defined by the list of IDRFs,
and confined to one body compartment
L2 Local-regional tumour with the presence of one or more IDRFs
M Distant metastatic disease (except stage MS tumour)
MS Metastatic disease in children younger than 18 months, with metastases confined
to the skin, liver and/or bone marrow
Source: Brisse et al. [3]
IDRFs image-defined risk factors
monoamine transporter (VMAT); once stored in granules, MIBG may be released

and taken up again through the same mechanism. The presence of these specific
uptake mechanisms (approximately 90 % of NB tumours express hNET) and the
prolonged intracellular storage provide the molecular basis for the specific imaging
and therapy with radioiodinated MIBG [9, 10]. Functional imaging with 123I-MIBG
scintigraphy is considered an essential tool in patients with NB both for initial stag-
ing – allowing visualization of the primary tumour and metastatic lesions in the
various sites – and response to therapy [3].
This chapter will focus on the role of MIBG scintigraphy for diagnosis and monitor-
ing of NB, with mention to compounds for positron emission tomography (PET) such
as fluorine-18-fluorodeoxyglucose (18 F-FDG), fluorine-18-dihydroxyphenylalanine
(18 F-DOPA), 68Ga-labelled somatostatin analogues, 11C-hydroxyephedrine (11C-HED)
and 124I-MIBG. Also the evolution in the use of 131I-MIBG therapy in high-risk NB
will be reviewed.
13.2 Available Diagnostic Tools in Neuroblastoma
Ultrasonography is a widely available, non-invasive and easy to perform imaging

technique, which is usually the first imaging modality to be used when an abdomi-
nal or pelvic tumour is suspected in a child. US allows accurate localization of the
abdominal or pelvic mass, also defining the relationship of the tumour with adjacent
organs and vessels [3]. CT and MRI are usually performed for assessing local dis-
ease and imaging defined risk factors. The wide availability of multidetector CT
machines allows to obtain images very quickly without motion artefacts, so limiting
the need for sedation. On the contrary, MRI has long imaging time with need for
sedation but has the advantage of higher contrast resolution and the lack of radiation
exposure. In any case, the superiority of MRI over CT for local disease assessment
has not been demonstrated, and the use of one modality or the other depends on
local availability and the radiologist’s preference [3].
Bone marrow involvement is assessed by bilateral bone marrow aspirates and
biopsy. Bone scan with 99mTc-diphosphonates was extensively used in the past for
the detection of bone metastases. A potential pitfall of bone scan is the high physi-
ologic uptake of the growing metaphysis in children, which may be misinterpreted
as metastases or hide small lesions. Currently, bone scintigraphy is usually not
required, except in cases with MIBG-negative primary tumour or when MIBG posi-
tivity cannot be confirmed, i.e. primary tumour removed before MIBG scan [3].
13.3 MIBG Scintigraphy: Technical Aspects
Procedure guidelines for image acquisition and analysis of MIBG scans in children
have been developed, aimed to achieve high-quality studies and a high degree of
reliability and reproducibility in interpretation [11–13].
13.3.1 Radiopharmaceutical
Both 131I- or 123I-labelled MIBG are available for diagnostic purposes. In children,
123
I-MIBG must be considered the tracer of choice for its lower radiation dose to
the patient and superior imaging characteristics: shorter physical half-life (13 h
for 123I versus 8 days for 131I), ideal photon energy for gamma camera and single-
photon emission computed tomography (SPECT) imaging (159 keV for 123I ver-
sus 364 keV for 131I) and lack of beta particle emission [14]. 123I-MIBG is
commercially available in Europe since the mid-1990s, while in the USA it has
been approved for clinical use in children by the Food and Drug Administration
in 2008.
13.3.2 Preparation and Interference
To protect the thyroid from unnecessary radiation dose, thyroid uptake is blocked
by the administration of saturated solution of potassium iodide administered
orally starting 1 day before 123I-MIBG administration and continuing for the dura-
tion of the scanning period. Dosage is chosen in accordance to local protocols or
European guidelines [11, 15]. In our centre we have adopted the following proto-
col: 2 mg/Kg per day of potassium iodide (Lugol’s solution 5 %: 1 mL = 130 mg
iodide; 1 gtt = 6.5 mg iodide), beginning 1 day before tracer injection and continu-
ing for 1–2 days. Alternatively, potassium perchlorate may be given at a dose of
8 mg/Kg three times daily, starting 2–24 h before tracer injection and continuing
for 2 days [13].
Many classes of drugs are known or are expected to alter MIBG uptake and/or
vesicular storage through various mechanisms and must be withdrawn before imag-
ing to avoid false-negative results (Table 13.3) [16]. The most commonly used in
children are the decongestant pseudoephedrine (a cold and cough preparation) and
the beta-adrenergic antagonist labetalol (for blood pressure control) [13]. Sedation
may be required due to the long scanning time, mainly in children between 1 and 3
years [13].
Table 13.3 Drugs known to interfere with MIBG

Suggested period
Mechanism of of withdrawal
interference Drugs (days)
Inhibition of Cocaine, opioids 7–14
uptake-1 Tricyclic antidepressants (amitriptyline and 7–21
derivatives, imipramine and derivatives,
amoxapine, loxapine, doxepin and others)
Antipsychotics (phenothiazinesa, thioxanthenes, 21–28
butyrophenones)
Labetalol, metoprolol 21
Inhibition of Reserpine, tetrabenazine, etc. 14
granular uptake
Competition for Norepinephrine, serotonin, guanethidine, etc. 14
granular uptake
Depletion of storage Reserpine, guanethidine, labetalol, etc. 14–21
granules Sympathomimeticsb (such as phenylpropanol- 14–21
amine, amphetamine, dopamine, isoproterenol,
salbutamol, etc.)
Increased uptake Calcium channel blockers 14
and retention Angiotensin-converting enzyme inhibitors 14
Source: Rufini et al. [16]
a
Occasionally components of antiemetic and antipruritic agents
b
Components of bronchodilators, decongestants and anoretics
13.3.3 Administered Activity
Some differences exist in the choice of administered activity of 123I-MIBG in chil-

dren between European and North American guidelines. The North American
Consensus Guidelines recommend administered 123I-MIBG activities of 0.14 mCi/
kg (5.2 MBq/kg) with a minimum of 1 mCi (37 MBq) and a maximum of 10 mCi
(370 MBq) [17]. In the paediatric dosage card by the European Association of
Nuclear Medicine (EANM), the administered activity is calculated by multiplying a
baseline activity by different multiples (weight- and radiopharmaceutical-dependent
factors) with a minimum activity of 37 MBq and a maximum activity of 400 MBq
for 123I-MIBG (EANM Dosage Card, Version 1.2.2014, www.eanm.org). In any
case, as sensitivity of MIBG scintigraphy increases with increased administered
activities and the risk of radiation hazard is less than the risk deriving from false-
negative results, it is of great importance to get high-quality images with adequate
counts [13]. To avoid adverse effects (tachycardia, pallor, vomiting, abdominal
pain), slow intravenous injection over the course of 1–5 min is recommended.
Central venous catheters should be avoided if possible; if these are utilized, they
should be flushed with saline solution (100–200 ml), to avoid artefacts in scinti-
graphic images. The radiation burden depends on administered activity and on the
child’s age; the effective dose is 0.037 mSv/MBq for a 5-year-old child and
0.068 mSv/MBq for a 1-year-old child [15].
13.3.4 Instrument Specifications
When 123I-MIBG is used, imaging is performed using a dual-head large-field-of-

view gamma camera equipped with a low-energy high-resolution collimator, energy
setting 159 keV, 15–20 % window. According to some authors, medium-energy
collimation is preferable for acquisition of both planar and SPECT 123I-MIBG
images with the aim of minimizing scatter [8]. The availability of SPECT/CT hybrid
systems equipped with high-resolution CT is currently growing; co-registered CT
images are utilized for attenuation correction and lesion localization.
13.3.5 Imaging Procedure
Standard imaging (planar and SPECT or SPECT/CT) is performed at 20–24 h after

123
I-MIBG injection. Additional planar images can be performed at 48 h to clarify
tracer accumulation in the kidneys or in the bowel. Anterior and posterior whole-
body images are acquired at a scan speed of 5 cm/min, with additional spot images
including lateral views of the skull; in alternative, both anterior and posterior static
spot views (about 500 kcounts or 10-min acquisition, 256 × 256 matrix; for the
upper and lower limbs, 75–100 kcounts may be sufficient) of the head (both antero-
posterior and lateral views are recommended), neck, chest, abdomen, pelvis and
upper and lower extremities. Planar images do not require computer analysis.
Single-photon emission tomography (SPECT) can improve diagnostic accuracy,

allowing better definition and localization of tumour deposits as well as the distinc-
tion between physiologic and abnormal uptakes [18]. SPECT is particularly useful
when uncertainty exists regarding lesion localization, for example, in distinguishing
between soft-tissue and skeletal lesions. Whenever possible, SPECT should be per-
formed even though sedation may be required. Acquisition parameters for SPECT
imaging depend on the available equipment; generally 360° rotation, 120 projec-
tions, 25–35 s per step and 128 × 128 matrix are used. Ideally, SPECT should cover
the thorax, abdomen and pelvis. In SPECT/CT imaging the CT scan should be
acquired with high resolution in order to provide better anatomical details. Also
reconstruction parameters for SPECT depend on the equipment and software
available.
13.4 MIBG Scintigraphy: Clinical Information
13.4.1 Principal Information, Pitfalls, Limitations
Knowledge of normal biodistribution of radioiodinated MIBG is essential to avoid

misinterpretation [19]. Normal scintigraphic pattern in children includes visualiza-
tion of the salivary glands, heart, liver, adrenals and urinary collecting system. The
myocardial uptake may be particularly intense in children under 6 months [19].
Tracer accumulation in the skeletal muscles, nasal mucosa, lungs, bowel and thy-
roid may also be seen. In children, bilateral symmetrical activity is sometimes evi-
dent in the neck and supraclavicular region, related to uptake in brown adipose
tissue, which is mediated by the sympathetic nervous system [20]. No skeletal
uptake is ever evident; the spine is represented by a vertical photopenic strip, and
the joints are seen as photon-deficient areas surrounded by background muscle
activity (Fig. 13.1a, b).
In NB patients, MIBG uptake is observed in the primary tumour and in meta-
static sites including the lymph nodes, liver, bone and bone marrow. Skeletal abnor-
malities can be observed either as focal areas of increased uptake, mostly reported
as cortical bone metastases (Fig. 13.2), or as a diffuse uptake, mostly reported as
bone marrow infiltration (Fig. 13.3). Recently, the existence of two MIBG-avid
metastatic patterns in newly diagnosed NB has been described: a “limited and focal”
pattern, found mainly in patients with MYCN-amplified NB, and an “extensive and
diffuse pattern” found mainly in patients with single-copy MYCN tumours; in
patients with MYCN-amplified NB, focal metastases had a better prognosis than the
other types of metastases [21].
False-positive results at MIBG scintigraphy are an uncommon finding, mainly
related to misinterpretation of physiologic uptake, i.e. as a result of radioactivity in
the urinary tract, or the presence of adrenal hyperplasia after contralateral adrenal-
ectomy [16]. Moreover, mature ganglioneuroma and other neuroendocrine tumours
may show MIBG uptake. SPECT images of the liver should be interpreted with
caution, due to heterogeneity of liver uptake; a relatively higher MIBG uptake in the
Fig. 13.1 (a) Normal biodistribution of 123I-MIBG. Note the vertical photopenic strip representing
the spine and the joints seen as photon-deficient areas surrounded by background muscle activity. (b)
123
I-MIBG left lateral and right lateral spot views of the head-neck and thorax. Note the bilateral
symmetrical activity in the supraclavicular region related to uptake in brown adipose tissue
left liver lobe has been reported [22]. The risk of false-positive findings due to mis-
interpretation of physiologic uptake is expected to be reduced by a more widespread
use of SPECT/CT.
False-negative findings at MIBG scintigraphy may be encountered, which are
caused by various factors [16]:
• Incorrect patient preparation, with reduced MIBG uptake by interfering drugs

• Technical factors, such as limited spatial resolution, with reduced sensitivity in
detecting small lesions
• Anatomical factors, such as tumour size and site (voluminous primary tumours
or physiologic uptake masking adjacent small tumour lesions)
• Biological factors depending on intrinsic tumour characteristics, such as tumour
heterogeneity, low or absent expression of hNET or rapid tracer washout from
the storage pool (Fig. 13.4)
a b c
Fig. 13.2 A 13-year-old boy with recurrent neuroblastoma. (a) 123I-MIBG anterior spot view of the
abdomen and pelvis showing a focal area of increased uptake in the left region of pelvic bone. Axial
(b) and coronal (c) 123I-MIBG SPECT/CT images. Note the cortical bone abnormality evident in the
CT images (arrow) and the corresponding area of increased tracer uptake at the fused images
Fig. 13.3 A 4-year-old boy with stage 4 neuroblastoma who previously undergone right adrenal-
ectomy. Note the diffuse skeletal uptake at the level of the skull, humeri, thoracic cage, spine,
pelvis, femora and tibia, related to extensive bone marrow involvement
13.4.2 Added Value and Clinical Indications
MIBG scintigraphy is a well-established procedure in the diagnostic manage-

ment of NB allowing visualization of primary and residual/recurrent tumours as
Fig. 13.4 A 5-year-old girl with a voluminous abdominal neuroblastoma evident at two represen-
tative axial-enhanced CT images (a) and showing no 123I-MIBG uptake (anterior and posterior spot
view of the lower chest, abdomen and pelvis) (b)
well as metastatic lesions in the bone, bone marrow, lymph nodes and other sites
with an overall accuracy of about 90 % and a detection rate for bone lesions of
about 95 % [16]. Since 1993 the INSS has adopted MIBG scintigraphy for ini-
tial staging and response evaluation after therapy [6]. According to the recent
INRG Staging System, 123I-MIBG scintigraphy is mandatory at staging; MIBG
findings unequivocal for metastatic disease do not require confirmation by other
imaging modalities [7]. The specificity of MIBG is close to 100 %. In assessing
response to therapy, MIBG scintigraphy is a very sensitive indicator of residual
active tumour. Performed at initial diagnosis and after induction chemotherapy,
it gives prognostic information, as a positive scan during and after induction
therapy or immediately before myeloablative therapy suggests a poor outcome
(Fig. 13.5a, b) [23, 24].
Fig. 13.5 (a) Planar spot views of 123I-MIBG scan in a 5-year-old girl with stage 4 neuroblastoma
MYCN amplified. The staging scan shows abnormal 123I-MIBG uptake in the right suprarenal region
and extensive bone involvement at the level of the skull, humeri, thoracic cage, spine, pelvis, femora and
left tibia. (b) 123I-MIBG scan performed to monitor the response to induction chemotherapy showing
persistent abnormal 123I-MIBG uptake in the right suprarenal region and extensive bone involvement
On the whole, MIBG scintigraphy is considered the most effective indicator of

NB with the following clinical indications:
• Staging of the disease at initial diagnosis

• Search of postsurgical residual tumours
• Evaluation of tumour response to treatment
• Early diagnosis of recurrence at follow-up in high-risk patients
• As a prelude to 131I-MIBG therapy
13.4.3 Criteria for Evaluation of Disease Extent
To evaluate the prognostic significance of disease extent at diagnosis and to estimate

the individual tumour burden of metastatic disease after therapy, various semi-
quantitative scoring systems have been developed for MIBG scintigraphy [25–28].
These scoring systems, which are quite similar with minor variations, aim to predict
the extent and the severity of MIBG-active disease as well as improve the concor-
dance between readers of MIBG scan [13, 29]. The body is divided into anatomical
regions (from 7 to 12 in the various systems); an individual score for extension of
metastatic involvement and intensity of uptake is assigned to each region. Soft-
tissue metastases may or may not be included in these scores. The validated semi-
quantitative scoring methods that are currently used have been reviewed, with
recommendations for their use in response assessment and prognostic evaluation
[13, 29]. The Curie scoring system has been validated in France and is now widely
used by the Children’s Oncology Group and the New Approach to Neuroblastoma
Consortium in the USA [8, 13]. The recently developed SIOPEN score is the one
currently used in Europe [13]. A significant prognostic impact of the initial MIBG
score and the pattern of MIBG uptake after chemotherapy in patients with stage 4
NB have been recently demonstrated, as higher MIBG scores at diagnosis and the
presence of any residual MIBG-positive metastasis after chemotherapy are predic-
tive of unfavourable outcome [30].
13.5 PET Radiopharmaceuticals for NB
In recent years, the functional imaging of NB has been enriched with the use of vari-
ous radiopharmaceuticals for positron emission tomography (PET). The major
advantages of PET imaging versus SPECT are the improved spatial resolution and
the shorter time of imaging (single acquisition on 1-day session). From a technical
point of view, the standard use of hybrid machines such as PET/computed tomogra-
phy (CT) allows to routinely correlate anatomic and functional information, thus
improving diagnostic accuracy.
A number of studies have confirmed the possibility of depicting NB lesions by
PET and PET/CT with 18 F-FDG. A weight-based activity per kg according to the
EANM (Version 1.2.2014, www.eanm.org) Dosage Card is administered. As FDG

uptake reflects glucose metabolism by cancer cells, FDG PET/CT is expected to be
useful for assessing those tumours which fail to accumulate MIBG due to reduced
expression of catecholamine transporters or pharmacological interference.
However, 18 F-FDG is less specific than MIBG, being concentrated in many tumour
types, including benign fibro-osseous lesions as well as in sites of infection/inflam-
mation [31]. The high physiologic brain activity can limit interpretation of 18 F-FDG
PET images by masking small skull lesions. Another limiting factor is the physio-
logic bone marrow activity during chemotherapy or under granulocyte colony-
stimulating factor, which can make bone marrow involvement after chemotherapy
difficult to visualize. When comparing MIBG scintigraphy with 18 F-FDG PET or
PET/CT in NB, MIBG appears to better depict disease extension in stage 4 NB
with metastatic involvement of the bone and bone marrow, while 18 F-FDG can be
especially useful for detecting soft-tissue sites of disease in the chest, abdomen and
pelvis due to the higher spatial resolution of PET technique [32, 33]. In clinical
practice, the use of 18 F-FDG PET/CT as a substitute of MIBG scintigraphy is cur-
rently not justified. However, in selected cases 18 F-FDG PET/CT may be useful as
a complementary imaging modality (Fig. 13.6). The main advantage of 18 F-FDG
PET/CT is in those cases that show faint or no MIBG uptake in NB lesions or in
case of discrepancies between morphologic imaging modalities and MIBG scintig-
raphy [8, 34, 35]. Besides disease detection, the results of 18 F-FDG PET/CT have
prognostic significance in high-risk NB, as intense metabolic activity in tumour
a b
Fig. 13.6 The same patient as in Fig. 13.4. 18 F-FDG PET/CT (a, b) performed at disease recur-
rence. (a) MIP (maximum intensity projection) image and (b) axial CT and fused images of
18
F-FDG PET/CT, showing abnormal tracer uptake in the chest, upper and lower abdomen and
bone corresponding to sites of disease recurrence
lesions exceeding the tumour avidity for MIBG is associated with more aggressive
disease and poor outcome [35].
New radiopharmaceuticals for PET imaging, which reflect different metabolic
pathways of NB cells, such as the uptake of hormone precursors (18 F-DOPA), the
expression of receptors (68Ga-labelled somatostatin analogues) or catecholamine
metabolism (124I-MIBG, 11C-HED), are currently under investigation.
18
F-DOPA PET/CT, which is considered a valuable tool in patients with pheo-
chromocytoma/paraganglioma and medullary thyroid carcinoma [36, 37], has been
recently proved to be a promising tool also in NB patients, for detecting relapse and
assessing the response to induction therapy [38, 39]. Administered activity is
4 MBq/kg [40]. When compared with 123I-MIBG scintigraphy, 18 F-DOPA PET/CT
seems to be more accurate in depicting primary tumours as well as small MIBG-
negative metastases [40, 41]. The predictive role of 18 F-DOPA PET/CT at the time
of suspected NB relapse has been recently investigated [42]. By applying an appro-
priate scoring system, the imaging scores proved to be related to patient outcome in
terms of progression-free survival and overall survival, with a significant positive
correlation between 18 F-DOPA PET/CT and MIBG scan. Prospective studies com-
paring these two imaging modalities at initial staging are required to assess diagnos-
tic accuracy and clinical impact of 18 F-DOPA PET/CT in NB.
Like other neuroendocrine tumours, NB is characterized by over-expression of
somatostatin receptors, mainly the subtype 2 [43]. In the past, somatostatin receptor
scintigraphy has been reported to visualize tumour sites in patients with NB with
lower sensitivity than MIBG scan (64 % versus 94 %) [44]. Nevertheless,
111
In-pentetreotide scintigraphy can provide prognostic information as a longer sur-
vival has been reported in patients with somatostatin receptor-positive NB [43, 44].
Recently, the rationale of the use of radiolabelled somatostatin analogues in NB has
been applied to PET radiopharmaceuticals. Preliminary data with 68Ga-peptides
report a high sensitivity of 68Ga-DOTATOC PET/CT in NB, >95 % [45]. Furthermore,
important therapeutic implications are inherent to the use of 68Ga-peptides in NB, as
a positive scan allows to select children who are candidates for radio-receptor ther-
apy with 90Y- or 177Lu-labelled somatostatin analogues [45, 46].
Due to the physical characteristics of iodine-124 (4.2 days half-life), MIBG
labelled with this positron emitter is particularly suitable for dosimetric estimates
[47]. Potential advantages are the use of a whole-body tomographic technique, the
high sensitivity and spatial resolution of PET device, the definition of heteroge-
neous uptake and quantitative data easy to be obtained. The main limitation of
124
I-MIBG remains the absence of clinical studies investigating its role in NB.
Another catecholamine analogue PET radiopharmaceutical is 11C-HED, which
has been used in NB by Shulkin et al. since 1996 giving high-quality functional
images within minutes after injection of 11C-HED [48]. However, the high renal
excretion of 11C-HED can limit the visualization of tumours close to the kidney, and
the high physiologic liver uptake can mask small liver metastases [49]. Finally, a
practical limitation is related to the short half-life of 11C (20 min) requiring an
on-site cyclotron.
13.6 Available Therapeutic Tools in Neuroblastoma
The therapeutic approach to NB depends on risk stratification, which is based on a

number of clinical and biological prognostic factors (see Sect. 13.1). According to
risk stratification, patients with NB are stratified in:
• Low risk, i.e. patients with small localized tumours and favourable tumour
biology
• Intermediate risk, i.e. patients with small localized tumours with unfavourable
tumour biology and patients with locally advanced tumours and favourable
tumour biology and metastatic disease in patients ≤18 months of age and favour-
able tumour biology
• High risk, i.e. patients with locally advanced tumours and unfavourable tumour
biology and metastatic disease in patients ≤18 months of age and unfavourable
tumour biology or metastatic disease in patients >18 months of age [2]
In low-risk NB, surgery is the treatment of choice with generally favourable out-
come. Patients with intermediate-risk NB generally respond well to moderate-
intensity chemotherapy and surgery. The most challenging group are patients with
high-risk NB, showing a high rate of relapse in the bone and bone marrow. These
patients are intensively treated by multi-agent chemotherapy, surgery, local radia-
tion therapy and high-dose therapy with autologous haematopoietic stem cell res-
cue. In patients who achieve remission, minimal residual disease is usually treated
by monoclonal antibodies directed against tumour cells as well differentiating
agents such as 13-cis-retinoic acid. Despite all these intensive therapies, less than
50 % of patients with high-risk disease will survive [2, 50].
Since its initial application, MIBG labelled with 131I has been used with success
for therapy of those neuroendocrine tumours showing intense uptake and prolonged
retention of the tracer, mainly pheochromocytomas, paragangliomas and NB. Since
the beginning, it was apparent that 131I-MIBG therapy had a significant palliative
effect in children with metastases and resistant/recurrent NB after conventional
treatment modalities had failed. The rapid relief of pain offered by MIBG therapy
without analgesics or other treatment modalities was remarkable [51]. Unfortunately,
after more than 25 years of clinical use, the precise role of 131I-MIBG in the thera-
peutic strategy of NB is not well defined and may still be considered to be investi-
gational. This is partly due to the lack of prospective randomized clinical trials, the
large variability of selection criteria and therapeutic protocols, the limited use of
dosimetry as well as logistic problems mainly related to radioprotection. From a
clinical point of view, even though 131I-MIBG used as monotherapy could give
about 30 % of objective responses, even long-lasting, it showed to be ineffective in
sustaining a permanent remission and could not avoid the unfavourable outcome of
the disease. Moreover, the clinical use of 131I-MIBG was somehow hampered by the
important myelotoxicity. So, various treatment regimens including 131I-MIBG have
been designed in the course of time to achieve greater antitumour efficacy and low
toxicity to normal tissues, with the aim of improving the cure rate of patients with
high-risk NB.
The results of a systematic review have been recently published [52]. The studies
included were characterized by large amount of heterogeneity with regard to patient
population, treatment schedule and response assessment; the mean objective tumour
response rate reported was 32 %. The authors concluded that 131I-MIBG is an active
treatment for NB, but its place in the management of NB remains unclear, underly-
ing the needs of prospective randomized trials [52].
131
13.7 I-MIBG Therapy: Technical Aspects
13.7.1 Radiopharmaceutical
High specific activity 131I-MIBG (up to 1.48 GBq/mg) is used, diluted with compli-
ance with the manufacturer’s instruction. A radiolabelled agent with a negligible
cold MIBG content has been synthesized, the so-called noncarrier-added MIBG
(nca-MIBG). Preclinical studies support the enhanced uptake of nca-MIBG com-
pared to the standard preparation [53]. The theoretical advantage of this formulation
for therapeutic application is the reduced molar amount of drug injected and conse-
quently its reduced pharmacological side effects. A dose-escalation study of nca-
MIBG labelled with 131I and used as a single agent for treating patients with relapsed
or refractory NB showed that nca-131I-MIBG is a tolerable, feasible and effective
radiopharmaceutical at activity levels that are comparable to carrier-added MIBG
[54].
13.7.2 Therapeutic Procedure
Procedure guidelines for MIBG therapy have been published in Europe [55]. In
synthesis, drugs that may reduce MIBG uptake and/or retention must be stopped
(see Sect. 13.3.2); thyroid 131I uptake is minimized by oral stable iodine, starting 1–2
days before treatment and continuing for 10–15 consecutive days. 131I-MIBG is
administered by slow intravenous infusion (about 1 h). Administered activities are
not standardized, varying in the different clinical trials, usually ranging between 3.7
and 11.2 GBq. Treatment can be repeated, according to the clinical trial. Patients are
kept in an isolated room with the bed surrounded by a mobile lead radiation shield
for 4–6 days, according to local legislation. During infusion and at least twice daily
afterward, children are subjected to continuous pulse, EKG and blood pressure
monitoring. Whole-body post-therapy scintigraphic images are obtained up to day
6. Appropriate personnel, radiation safety equipment and procedures for waste han-
dling and disposal and for handling of contamination are required [55]. Children
undergoing MIBG therapy should be managed jointly by nuclear medicine physi-
cians and paediatric oncologists. Carers of children treated with 131I-MIBG must
receive specific instructions with regard to radiation safety precautions.
131
13.8 I-MIBG Therapy: Clinical Application
13.8.1 MIBG as Monotherapy in Resistant/Recurrent Disease
Early studies with 131I-MIBG as a single therapeutic agent could demonstrate a

20–37 % objective response rate, providing important palliation and improving
the quality of life of affected children [56–58]. These results were significant,
considering that most of these patients had advanced relapsed/refractory disease
and were treated with 131I-MIBG as a single agent after other treatment modalities
had failed [56].
In the evolution of the use of 131I-MIBG therapy in NB patients, an important step
has been achieved by the phase I study by Matthay et al. where incremental doses
of 131I-MIBG (from 2.6 to 18.2 mCi/Kg) were administered to obtain optimum ther-
apeutic effect, while at the same time the tumour-free marrow was cryopreserved
for autologous stem cell rescue. The results of this study are very important, dem-
onstrating that with stem cell rescue much higher activities of 131I-MIBG (>12 mCi/
Kg) can be administered [59, 60].
13.8.2 MIBG as Front-Line Therapy
The positive results observed in pretreated patients led to explore the possibility
of using 131I-MIBG at the time of diagnosis for induction therapy prior to surgery
(“front-line” or “de novo” therapy). The rationale of this strategy is that pretreat-
ment with chemotherapy may have a negative effect on tumour avidity of
131
I-MIBG and may contribute to a greater toxicity. Experience with front-line
therapy has been carried out by the Amsterdam group and the Rome group
[61–63]. Results were comparable to those of induction with chemotherapy but
with lower toxicity; however, survival rates were not higher compared to high-
dose chemotherapy.
13.8.3 MIBG in Combination with Other Therapies
Important obstacles in achieving a cure with 131I-MIBG may be due to inadequate

dose, poor targeting of micrometastases, emergence of resistant clones, suboptimal
concentration of radioisotope in the tumour cells or insensitiveness to radiation
[64]. In an attempt to overcome these problems, many different kinds of interven-
tional and adjunctive regimen evolved. Among these, the integration of MIBG ther-
apy with chemotherapy or other agents such as monoclonal antibodies and
biotherapeutics was suggested [65]. The combined use of chemotherapy and
131
I-MIBG is based on findings of in vitro studies demonstrating a synergistic action
between different agents leading to enhanced expression of the norepinephrine
transporter (NET) gene in the tumour and thereby increasing the accumulation of
131
MIBG [66]. In this setting, strategies to increase the efficacy of I-MIBG in NB
have been developed in clinical trials. Among these:
131
• I-MIBG therapy combined to chemotherapy agents known to be active in NB
(cisplatin and cyclophosphamide or these agents combined to etoposide and vin-
cristine), to avoid the development of resistant tumour clones [63]
• 131I-MIBG therapy combined to radiation sensitizers, which potentiate the antitu-
mour effect of 131I-MIBG and protect normal tissues from radiation (topotecan,
irinotecan) [67]
• 131I-MIBG combined to drugs which increase NET expression (vorinostat) [68]
Other combination methods include intensive multi-agent chemotherapy and

haemopoietic stem cell rescue with high-dose carboplatin and melphalan or whole-
body irradiation following 131I-MIBG treatment [69, 70].
13.8.4 Side Effects
The most frequent and significant toxic effect of 131I-MIBG therapy is myelotoxic-
ity, mainly transient thrombocytopenia and leucopenia. This is thought to be partly
due to radiation crossfire to the bone marrow from 131I-MIBG-targeted cells [71–73]
and partly as a consequence of selective binding of 131I-MIBG to megakaryocytes
[74]. The severity of thrombocytopenia, however, appears to correlate to some
extent with the duration of previous therapy, the number of courses administered
and the presence of massive bone marrow infiltration. Myelosuppression occurs
within 2–4 weeks after therapy; the nadir is usually observed after 4–6 weeks.
The non-haematological toxicities frequently encountered are nausea and vomit-
ing, mainly within the first 48 h. Other additional side effects have been reported:
• Changes in blood pressure, which typically occur within the first 48 h after tracer
administration [59, 75, 76].
• Hypothyroidism, mainly subclinical, occurring in about 25 % of patients despite
thyroid blockade, due to the uptake of free 131I by the thyroid [59, 75, 77].
• Secondary malignancies, including solid tumours (such as sarcoma, malignant
schwannoma and fibrous histiocytoma) and leukaemia, mainly in patients who
previously received intensive chemotherapy [78, 79]. These secondary neo-
plasms have been reported in less than 4 % of treated patients; in any case, the
risk of this complication is far lower than the risk of disease progression [79].
• Deterioration in renal function has been occasionally noted, which is likely to be
due to compromised renal function in intensely pretreated patients [80].
In conclusion, MIBG scintigraphy is an essential diagnostic tool in the hands of

clinicians for assessing children with NB, both at initial diagnosis and for response
evaluation. Despite that alternative diagnostic procedures, such as PET with
18
F-DOPA, have shown preliminary promising results, the role of MIBG scintigraphy
in routine clinical practice remains unique, since its capital contribution in the pre-
therapeutic evaluation before 131I-MIBG radionuclide therapy. Regarding therapy,
since its initial application, the role of 131I-MIBG evolved with time. Initial success in
the palliation of symptoms in advanced/resistant NB was followed by several different
ways of application of MIBG therapy with the hope of attaining a lasting remission or
cure. The combination of 131I-MIBG with chemotherapy or other agents in pretreated
resistant disease seems to be very encouraging in terms of degree and rapidity of
response. Moreover, bone marrow harvesting has become an established option to
circumvent fatal myelotoxicity. As more knowledge accumulates on the molecular
characteristics of NB, it appears that the full therapeutic potentiality of 131I-MIBG is
yet to be realized through integration with molecular methods and genetic therapy.
Studies are in progress with the aim to explore the possibility of using a cocktail of
radiopharmaceuticals (131I-MIBG and radiolabelled somatostatin analogues) with the
aim of adding together the therapeutic efficacy of each agent [81].
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Pediatric Sarcomas
14
Natale Quartuccio, Leonard Wexler, and Heiko Schöder
Contents
14.1 Clinical Information 280
14.1.1 Rhabdomyosarcoma 280
14.1.2 Osteosarcoma 281
14.1.3 Ewing Sarcoma 282
14.2 Imaging Tests in Pediatric Sarcomas: Overview 282
14.3 Principal Information Provided by Nuclear Medicine Techniques
and Comparison to Other Imaging Modalities 296
14.3.1 Bone Sarcomas 296
14.3.2 Rhabdomyosarcoma 297
14.4 Potential New Developments 298
14.5 Summary and Take-Home Message 298
References 299
N. Quartuccio, MD
Nuclear Medicine Unit, Department of Biomedical Sciences, University of Messina, Messina,
Italy
Wolfson Molecular Imaging Centre, University of Manchester, 27 Palatine Road, Manchester,
Withington M20 3LJ, UK
e-mail: natale.quartuccio@manchester.ac.uk
L. Wexler, MD
Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
H. Schöder, MD (*)
Department of Radiology, Molecular Imaging and Therapy Service (MITS),
Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA
e-mail: schoderh@mskcc.org

DOI 10.1007/978-3-319-21371-2_14
280 N. Quartuccio et al.
14.1 Clinical Information
Pediatric sarcomas are broadly defined into two main groups: (a) tumors that arise pri-
marily in bone (osteosarcoma [OS] and Ewing sarcoma [ES], although the latter may
also arise in extraosseous locations), and (b) tumors that arise in muscle and associated
connective tissues (rhabdomyosarcoma [RMS] and the larger group of non-rhabdo soft
tissue sarcomas [NRSTS]). Collectively, these tumors account for fewer than 1500
cases in children and adolescents in the USA, with an annual incidence of about 440
cases of OS, 400 cases of RMS, 250 cases of ES, and 200 cases of NRSTS [1, 2]. This
chapter will focus on the three most common tumor types – RMS, OS, and ES.
14.1.1 Rhabdomyosarcoma
Rhabdomyosarcoma in the pediatric population is comprised of two main histologic

subtypes: embryonal subtype, which occurs in about 65–75 % of patients, and alveo-
lar subtype. The median age at diagnosis is 6 years; two-thirds of cases arise prior to
age 10. Embryonal tumors occur in excess in patients with “cancer susceptibility
syndromes” including Li-Fraumeni syndrome (p53 mutation), neurofibromatosis
(NF-1 and NF-2) mutation, and Beckwith-Wiedemann syndrome. Alveolar tumors
typically arise in unfavorable locations, are disproportionately more common in ado-
lescents, and present with a significantly greater risk of concurrent regional nodal
and/or distant metastatic disease; these tumors have a defining and probably causative
genetic abnormality involving a reciprocal translocation between the FOXO1 gene
on chromosome 13 and either the PAX3 gene on chromosome 2 or, less commonly,
the PAX7 gene on chromosome 1. Rhabdomyosarcomas may arise in any part of the
body, but the most common locations include the head and neck (35–40 % of the
total), genitourinary tract (20–25 %), and the extremities (20 %). Although all patients
are presumed to have at least micrometastatic disease at the time of initial diagnosis,
only one patient in five or six will have radiographic evidence of distant metastases.
Regional lymph node sampling for staging is only performed in boys aged 10
years or older with paratesticular tumors; in these patients, ipsilateral retroperito-
neal lymph node sampling is recommended because regional nodes are involved by
disease in approximately 40 % and because current clinical imaging tests have
insufficient sensitivity for detecting small-volume nodal metastases. Regional
lymph node sampling is also recommended in patients with extremity tumors
because the incidence of nodal metastases is at least 20 %. When nodal metastases
are present, the chance for cure decreases markedly. More recently, a revised stag-
ing approach, which is based on the clinical and histologic features predictive of
distant metastases, has been recommended [3].
Overall survival for patients with RMS exceeds 70 %. Patient outcome can be
stratified by risk classification into three broad groups: (a) Low-risk patients have
either nonmetastatic embryonal tumors arising in “favorable” sites (orbit, non-
parameningeal head and neck, paratestis, female GU tract), regardless of tumor size
or initial surgical resectability, or nonmetastatic embryonal tumors arising in
14 Pediatric Sarcomas 281
unfavorable sites that are completely or gross totally resected. This group comprises
approximately one-third of all newly diagnosed RMS. Cure rates of 75–90 % can be
achieved with chemotherapy, sometimes supplemented by radiotherapy. (b)
Intermediate-risk patients have either unresected nonmetastatic embryonal tumors
arising in unfavorable locations (bladder, prostate, extremity, parameningeal) or
nonmetastatic alveolar tumors regardless of the site of origin. Cure rates of 50–70 %
are possible with modern chemotherapy (3–5 drugs over 9–12 months) supple-
mented by radiotherapy for local control. (c) High-risk patients have metastatic
tumors of either histology. Cure rates range from 10 % or less (in widely metastatic
alveolar tumors) to nearly 50 % (in patients <10 years old with embryonal tumors
and isolated lung metastases) using intensive chemotherapy regimens (5–7 drugs
over 1 year) supplemented by radiotherapy for local control. In the USA, most
patients with RMS are treated according to cooperative group treatment protocols.
Over the past 25 years, the prognosis and risk of late effects have improved for
patients with low-risk tumors, but very little improvement in outcome has been
accomplished in patients with intermediate- and high-risk tumors.
14.1.2 Osteosarcoma
OS is most commonly diagnosed in adolescents in the distal femur, proximal tibia,

or proximal humerus. Microscopically, tumors may be primarily osteoblastic, chon-
droblastic, fibroblastic, telangiectatic, or, rarely, a combination of these features. OS
is generally considered a high-grade malignancy with uniform metastatic potential,
although a low-grade surface lesion can also be seen. Overt metastatic spread, over-
whelmingly limited to the lungs, occurs in about 10–20 % of patients. No common
cytogenetic or molecular abnormality has been identified in OS. However, patients
with germline RB and p53 mutations are at higher risk for OS. In addition, activa-
tion of the growth hormone-insulin-like growth factor axis may also contribute to
the development of these tumors.
Traditionally, the staging of OS has included MRI of the affected extremity to
define the anatomy of the primary tumor (particularly with regard to its intraosseous
extent toward or through the growth plate and its extraosseous extent with regard to
displacement or encasement of nearby neurovascular structures), CT chest to evalu-
ate for lung metastases, and a bone scan for evaluating the activity of disease at the
primary site as well as presence and extent of distant osseous disease. Several stag-
ing systems are in use, but the only clinically relevant distinction is between patients
with and patients without distant metastases, with corresponding cure rates of about
65 % versus 20 % or less. Treatment usually includes neoadjuvant chemotherapy
over 9–10 weeks with cisplatin, doxorubicin, and high-dose methotrexate. The
majority of patients then undergo limb-sparing resections using implanted endo-
prostheses. Response to neoadjuvant chemotherapy, measured by the percent necro-
sis in tumor specimen at the time of surgery, correlates with prognosis: The best
long-term outcome is observed when tumor necrosis is >90 %, leading to long-term
survival of greater than 80 %.
14.1.3 Ewing Sarcoma
ES is a prototypical small, round blue cell tumor of childhood. It belongs to a

“family” of tumors that include peripheral neuroepithelioma or peripheral neuroec-
todermal tumor (PNET) and share a defining molecular abnormality involving a
reciprocal translocation between the FLI1 gene on chromosome 11 and the EWS
gene on chromosome 22.
Unlike OS, where more than three-quarters of tumors arise around the knee or
shoulder joints, nearly half of ES arise in the axial skeleton (pelvic bones, less com-
monly also in the ribs/chest wall, scapulae, or vertebrae). Appendicular tumors
more commonly arise in the diaphysis rather than in the metaphysis. ES is slightly
more common in males. Most cases present in the second decade of age (up to 1/3
of cases may be diagnosed prior to age 10). For unclear reasons, ES is rarely seen in
Africans or individuals of African ancestry.
Patients with newly diagnosed ES typically undergo baseline MRI and/or CT scans
of the primary tumor site, CT of the chest to evaluate for lung metastases, a bone scan
to evaluate for osseous metastases, and bilateral iliac crest bone marrow aspirations
and biopsies. There is growing interest in using FDG PET as a staging tool and to
assess response to therapy; some centers are now using PET as the preferred and only
nuclear medicine imaging test. Distant metastatic disease is seen in approximately
20–25 % of newly diagnosed patients and most commonly involves the lungs, bones,
or bone marrow; lymph node involvement is rare. Overall, 65–75 % of patients with
nonmetastatic tumors, and 10–25 % of patients with metastatic tumors, can be cured
with modern therapy. Younger age, tumor size less than 8 cm, an appendicular pri-
mary site, and the absence of metastatic disease are all favorable prognostic factors.
Treatment starts with neoadjuvant chemotherapy (3-6 alternating cycles of vin-
cristine, doxorubicin, and cyclophosphamide (CAV), and ifosfamide with etoposide
(IE)), which usually leads to prompt and significant symptomatic improvement and
radiographic regression. This is followed by surgical resection (typically with endo-
prosthetic or allograft reconstruction) or definitive radiotherapy to the primary tumor
site and further chemotherapy for about 8–12 months. Similar to OS, patients with
nonmetastatic disease whose tumors show greater than 90 % necrosis at the time of
definitive surgery have better long-term survival (80 % versus 50 % if the primary
tumor remains largely viable). In patients with distant metastases at the time of
original diagnosis and in those who recur, long-term survival is rare.
14.2 Imaging Tests in Pediatric Sarcomas: Overview
In RMS, the most common sites for metastases are the lungs, bones, and/or bone
marrow (Fig. 14.1a–o). Historically, staging studies have included CT or MRI to
evaluate the primary tumor and its relationship to surrounding structures, CT of the
chest to evaluate for pulmonary metastases, a bone scan to evaluate for osseous
metastases, and bilateral iliac crest bone marrow aspirations and biopsies to evalu-
ate for metastatic marrow infiltration. More recent studies have focused on the role
of FDG PET in staging and assessment of response to therapy.
Fig. 14.1 Rhabdomyosarcoma. This patient presented with severe back pain, which proved to be
secondary to metastatic RMS. Clinical work-up led to an FDG PET/CT (a–i). The MIP image (a)
shows abnormal FDG uptake in L3 and also in the scalp. Transaxial CT and PET/CT fusion images
showed abnormal FDG uptake in the L3 vertebra (b, c), corresponding to a compression fracture,
an FDG avid right paraspinous soft tissue mass (d, e) with extension of FDG uptake into L3 verte-
bra and right neural foramen, and nodular scalp metastases (f, g). (h–j) An MRI (transaxial T1
images pre and post contrast) better defines the compression fracture and paraspinous disease. This
was proven to be metastatic RMS. The asymptomatic primary tumor was found on the PET/CT of
the lower extremities: MIP (k) and transaxial CT and PET/CT fusion images (l, m) show an FDG
avid soft tissue nodule in the distal left foot. (n) Incidentally, a bone scan with Tc99m MDP shows
increased tracer uptake in the L3 vertebra, but this study does not contribute any information that
could not be derived (and better defined) by PET/CT. Bone scans contribute very little, if any, clini-
cally relevant information in patients with RMS. All arrows are pointing at tumor sites
b c
d e
f g

h
i j

l m

X-ray plain films remain essential for the primary assessment of bone tumors,
even in the era of tomographic and molecular imaging; however, lytic lesions, prin-
cipally occurring in Ewing’s sarcoma, remain undetectable on plain films until
demineralization has reached 30–50 %. Some features that should be investigated on
plain radiographs and may aid in the differential diagnosis include an assessment of
the primary tumor matrix, presence or absence of margins around the primary bone
lesion, presence of corticalis destruction, presence and configuration of periosteal
reaction, and presence of new bone formation. OS (Fig. 14.2a–i) usually occur in the
epiphysis, ES usually in the meta- and diaphysis (Fig. 14.3a–r). The 3-phase bone
scan is still occasionally employed in the initial work-up of suspected bone tumors.
Unfortunately, the findings are not specific although most malignant tumor will
present with increased tracer uptake in all 3 phases of the scan. In particular in
patients with OS, a whole-body bone scan may detect possible osseous metastases,
as well as soft tissue metastases that contain a sufficient amount of osseous matrix
leading to tracer retention. Whole-body scans are obtained 2–4 h after injection of
Tc99m MDP. The amount of injected activity is based on body weight or body sur-
face area. Guidelines for appropriate activities have been published by both EANM
and SNM. Standard planar images of the torso can be supplemented by spot views
of regions of interest if clinically necessary. SPECT or SPECT/CT is rarely per-
formed because the yield of new and clinically relevant finings is low. The main
imaging tests for malignant bone tumors are CT, MRI, and, increasingly, FDG
PET. CT and MRI define the local extent of the primary tumor, any soft tissue
involvement, and the relationship to neurovascular structures. However, peritumoral
edema may lead to uncertainty in defining the exact tumor margins [4]. High-
resolution CT of the lungs remains the most sensitive test for the detection of pulmo-
nary metastases. High-pitch CT may reduce breathing and pulsation artifacts and
may also lower the radiation dose to the patient [5]. FDG PET shows a high sensitiv-
ity for primary and recurrent tumors with sensitivities in the 85–95 % range [6, 7].
A recent meta-analysis studying the role of FDG PET and PET/CT in ES showed a
high overall pooled sensitivity of 96 % and specificity of 92 % for both primary stag-
ing and restaging [8]. SUV numbers for OS and ES vary widely, from as low as 3.0
to as high as 20 [9]. However, it should be noted that aggressive benign bone lesions
cannot be distinguished from sarcomas on PET alone. Some benign lesions, such as
giant cell tumors, may show very high FDG uptake and SUV; conversely, some
malignant tumors, in particular chondrosarcomas, show relatively low FDG uptake.
Moreover, false-positive FDG uptake may occur at fractures, sites of infections, or
inflammations (such as periostitis). Thus, the primary purpose of FDG PET lies in
the evaluation for distant disease, in detection of possible recurrence, and increas-
ingly in monitoring the response to neoadjuvant and adjuvant chemotherapy.
With very few exceptions (so-called osteosclerotic variant), ES is an osteolytic
tumor and marrow-infiltrating tumor. Therefore, bone scans, which are generally
more sensitive for osteoblastic lesions, may not be very informative in ES. Instead,
distant disease is assessed better by FDG PET/CT or PET/MRI. In contrast, bone
scans are quite sensitive for OS metastases because of the intense osteoid produc-
tion and osteoblast activity in these lesions.
a b
Fig. 14.2 Osteosarcoma. Newly diagnosed OS in a young patient with upper arm pain. (a, b) The
plain radiograph shows a mixed lytic and sclerotic lesion with periosteal reaction and circumferential
soft tissue mass. (c–e) Three-phase bone scan with Tc99m MDP performed at baseline shows
increased radiotracer accumulation in the proximal left upper arm in the blood pool phase (c) and
intense uptake in the metaphysis of the left humerus on the delayed images (d). The remainder of the
bone scan is normal, thus excluding metastatic spread to other parts of the skeleton. (e–g) MRI
images (sagittal T1 and fat-saturated axial T1 pre and post contrast) again show the primary tumor in
the proximal humerus, predominantly subperiosteal circumferential soft tissue mass with thickness
of up to 1.2 cm, and some penetration through the periosteum into adjacent soft tissues. There are also
some prominent left axillary lymph nodes. (h) A follow-up bone scan after 3 months of neoadjuvant
chemotherapy shows abnormal uptake in the proximal left humerus, similar to the appearance on
baseline scan. Two weeks later, the patient underwent radical resection of the proximal left humerus
with allograft placement (i); image I shows the status post resection and repair. The resected tumor
measured 8.5 × 3.4 × 3.0 cm and was completely necrotic (100 % necrosis, grade 4 response). This
case demonstrates that bone scan findings cannot be used to assess the response to chemotherapy. All
arrows are pointing at tumor sites

e
g
h i

Fig. 14.3 Ewing sarcoma. ES primary

tumor in the left posterior chest wall with
widespread metastatic disease. This
adolescent patient initially presented with
left shoulder pain and was misdiagnosed
with tendinitis. Several weeks later, the
patient palpated a lump in the chest wall,
which led to further work-up and proper
diagnosis. (a–g) FDG PET/CT:
Maximum intensity projection (MIP; a)
and transaxial images at baseline (b, c)
show a hypermetabolic left posterior
chest wall mass also involving pleura and
lung. Numerous hypermetabolic
metastases are seen in lungs (d, e), lymph
nodes, and bones. (h–l) A follow-up
PET/CT after 5 months of chemotherapy
showed significant response with near
resolution of primary tumor and
metastases on MIP image (h) as well as
on transaxial CT and PET/CT fusion
images in the chest wall (i, j) and pelvic
bones (k, l). The patient then underwent
intensity-modulated radiotherapy (IMRT)
to the chest wall, lungs, and ribs. PET/CT
after completion of radiotherapy showed
stable minimal uptake in a left femoral
and right rib lesion. Approximately 1
year later, the patient noticed dark
coloration of urine, and a clinical exam
revealed minor jaundice. (m, n) PET/CT
at that time showed new widespread
metastatic disease that also involved the
head of pancreas. (o) This was confirmed
by subsequent MRI (axial T1 post
contrast) that confirmed presence of a
3.4 × 2.3 cm mass in the pancreatic head.
(p, q) Incidentally noted on PET/CT is
mild FDG uptake surrounding distal left
femur, status post radiotherapy to a single
residual osseous metastasis at this site.
This is a typical finding after localized
radiotherapy. All arrows are pointing at
tumor sites, except in (p) where the
arrow points at postradiation
inflammation in muscle
a
b c
d e
f g

h
i j
k l
m n

p q
Nowadays, FDG scans are performed as PET/CT with 3D PET. If a dedicated CT

scan of the torso has been ordered, it should be done in the same setting as the PET
scan, using higher (as appropriate for patient age) dose settings. In this case, the
usual low-dose CT of the PET/CT can be eliminated, and the data from the dedi-
cated CT are used for PET attenuation correction, thus reducing overall radiation
burden to the patient. The PET field of view should extend from the skull base to the
proximal thighs unless the primary tumor is located more distally. Routine imaging
of the lower extremities is not necessary in patients with primary tumor in the head
and neck region or trunk [10] because the diagnostic yield is extremely low. The
application of combined PET/MRI [11] in pediatric patients is of growing interest
because this may lower the radiation dose from medical imaging [12] and possibly
enable us to address a series of diagnostic and prognostic questions in one setting.
14.3 Principal Information Provided by Nuclear Medicine

Techniques and Comparison to Other Imaging
Modalities
14.3.1 Bone Sarcomas
FDG PET/CT is by definition a whole-body imaging modality and may therefore

detect potential sites of distant disease that are out of the limited field of view of CT
and MRI. It is therefore a good staging test for potential distant disease. However,
the sensitivity for lung metastases is limited, in particular for small nodules
<6–8 mm; their FDG uptake may be quite low and may be further underestimated
because of partial volume effects from respiratory motion during the PET acquisi-
tion. Small nodules at the lung base may be obscured if the CT is performed as
low-dose scan without breath-hold in deep inspiration. Occasionally, FDG PET
may be helpful when CT or MRI cannot distinguish between probable recurrence
and postsurgical changes. As a caveat, false-positive FDG uptake may occur sec-
ondary to inflammation and persistent bone remodeling.
The intensity of FDG uptake in the primary or recurrent tumor may provide
diagnostic and prognostic information. In general, low-grade tumors tend to show
lower FDG uptake than high-grade tumors although no clear cutoff can be identified
[13]. Tumors with higher cellularity also tend to have higher SUV. Accordingly,
biopsies should be directed to the tumor site with highest SUV, to identify the most
aggressive pathology, which in turn determines treatment decisions and prognosis.
High FDG uptake, expressed as SUV number or tumor to normal tissue ratio, is
associated with worse prognosis in patients with OS (shorter overall survival and
event-free survival) [14, 15]. FDG metabolic tumor volume also predicts patient
outcome [16]. Similar data have been published for ES.
The response to neoadjuvant chemotherapy can be monitored with PET. In one
study in patients with OS or ES, a higher initial FDG SUV and greater decline in
SUV (but not change in tumor size on MRI) after chemotherapy predicted a good
histologic response [7].
In some studies, patients with OS or ES and residual SUV of 2.5 after neoadju-
vant chemotherapy or with at least 50 % decline from baseline SUV experienced
better progression-free survival [17, 18]. In a group of 65 patients that also included
25 pts with either OS or ES, early changes in SUV at mid treatment further refined
the prognostic information that could be derived from baseline and end of induction
SUV [19]. In general, a greater decline in FDG SUV or MTV indicates greater sen-
sitivity to chemotherapy and therefore is also considered a surrogate for better out-
come after completion of combined modality therapy. In patients with OS who were
imaged with PET/MR, early changes in FDG SUV or MTV (but not changes on
MR) after one cycle of neoadjuvant chemotherapy predicted histologic response in
the surgical specimen [20]. (Recall that histologic response is the established and
clinically meaningful predictor of ultimate patient outcome after completion of all
therapy.)
14.3.2 Rhabdomyosarcoma
In the initial evaluation of soft tissue sarcomas, MRI is essential to define the local extent
of the disease; CT and FDG PET/CT (ideally performed as a single test) are important
to evaluate for spread of disease to locoregional lymph nodes and distant sites. Bone
scans provide no essential information that could not be derived from PET/CT and
should no longer be performed as a routine staging test in RMS. Bone and bone marrow
involvement are identified with high accuracy by PET/CT. The field of view for the
PET/CT should be tailored to the location of the primary tumor and expected pattern of
metastatic spread. Routine imaging of lower extremities, in particular in patients with
primary tumor in the head and neck region, does not appear meaningful. The CT remains
essential for the detection of small pulmonary nodules [21, 22].
The prognostic value of FDG SUV at the initial staging remains somewhat con-
troversial. Some studies suggested that high FDG uptake at primary or metastatic
sites may indicate a worse prognosis [23, 24], but other groups could not confirm
this observation. A negative PET after completion of combined chemo- and radio-
therapy is associated with better long-term recurrence-free survival. The role of
FDG PET for early response assessment in RMS is under investigation.
14.4 Potential New Developments
It is likely that combined PET/MRI will play a prominent role in the imaging of
pediatric patients with sarcomas. Although this will reduce radiation dose to
patients, it should be kept in mind that doses from PET/CT can also be reduced
when using modern equipment. There is currently no proof that PET/MR provides
more accurate information than PET/CT. Imaging time, potential need for sedation
during imaging, and cost of each test also need to be considered when selecting the
most appropriate test or a combination of tests for a given patient. Other recent
developments include the evaluation of alternate radiotracers in pediatric sarcomas,
including FLT, 11C, or 18F choline, as well as various amino acids and hypoxia mark-
ers. It will be important to demonstrate that any of these agents have advantages
over the proven and tested FDG. For instance, some claims that choline or amino
acids provide fewer false-positive findings have been difficult to reproduce. On
other fronts, the role of diffusion-weighted MRI (DWI) for staging and response
assessment is under investigation. Changes in the apparent diffusion coefficient
under therapy (delta ADC), but not changes in MRI tumor volume, may predict
treatment response [25]. These interesting preliminary data remain to be confirmed
in larger patient groups with various sarcoma histologies. In the end, the combina-
tion of PET and advanced MRI may provide the most accurate staging and response
assessment for pediatric sarcomas.
14.5 Summary and Take-Home Message
FDG PET/CT has become an essential imaging test in the staging and response
assessment of pediatric sarcomas. MRI provides the most meaningful information
in the local staging of disease, in particular to define the relationship to adjacent soft
tissue and neurovascular structures. CT remains essential for the detection of small
lung metastases. FDG PET also allows for early response assessment in patients
undergoing neoadjuvant chemotherapy or definitive chemoradiotherapy. In the
future, combined PET/MR may find application for the imaging of pediatric sarco-
mas. There remain hardly any indications for conventional bone scans with Tc99m
MDP, with the possible exception of initial staging of OS and work-up of rare osteo-
sclerotic variants of ES.
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and young adults 15 to 29 years of age, including SEER incidence and survival: 1975–2000.
National Cancer Institute, Bethesda, NIH, 2006
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bone tumors. In: Bleyer A, OLM Barr R, Ries LAG (eds) Cancer epidemiology in older ado-
lescents and young adults 15 to 29 years of age, including SEER incidence and survival:
1975–2000. National Cancer Institute, Bethesda, NIH Pub. No. 06-5767, 2006
3. Weiss AR, Lyden ER, Anderson JR et al (2013) Histologic and clinical characteristics can
guide staging evaluations for children and adolescents with rhabdomyosarcoma: a report from
the Children’s Oncology Group Soft Tissue Sarcoma Committee. J Clin Oncol 31:3226–3232
4. Quartuccio N, Cistaro A (2014) Primary bone tumors. In: Cistaro A (ed) Atlas of PET/CT in
pediatric patients. Springer, Milan, pp 67–86
5. Tsiflikas I, Thomas C, Ketelsen D et al (2014) High-pitch computed tomography of the lung
in pediatric patients: an intraindividual comparison of image quality and radiation dose to
conventional 64-MDCT. Rofo 186:585–590
6. Volker T, Denecke T, Steffen I et al (2007) Positron emission tomography for staging of pedi-
atric sarcoma patients: results of a prospective multicenter trial. J Clin Oncol 25:5435–5441
7. London K, Stege C, Cross S et al (2012) 18F-FDG PET/CT compared to conventional imaging
modalities in pediatric primary bone tumors. Pediatr Radiol 42:418–430
8. Treglia G, Salsano M, Stefanelli A, Mattoli MV, Giordano A, Bonomo L (2012) Diagnostic
accuracy of (1)(8)F-FDG-PET and PET/CT in patients with Ewing sarcoma family tumours:
a systematic review and a meta-analysis. Skeletal Radiol 41:249–256
9. Charest M, Hickeson M, Lisbona R, Novales-Diaz J-A, Derbekyan V, Turcotte R (2009) FDG
PET/CT imaging in primary osseous and soft tissue sarcomas: a retrospective review of 212
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12. Schafer JF, Gatidis S, Schmidt H et al (2014) Simultaneous whole-body PET/MR imaging in
comparison to PET/CT in pediatric oncology: initial results. Radiology 273:220–231
13. Folpe AL, Lyles RH, Sprouse JT, Conrad EU 3rd, Eary JF (2000) (F-18) fluorodeoxyglucose
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ables in bone and soft tissue sarcoma. Clin Cancer Res 6:1279–1287
14. Franzius C, Bielack S, Flege S, Sciuk J, Jürgens H, Schober O (2002) Prognostic significance
of (18)F-FDG and (99m)Tc-methylene diphosphonate uptake in primary osteosarcoma. J Nucl
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nostic value of (1)(8)F-FDG PET/CT in the initial assessment of high-grade bone and soft tissue
sarcoma. A retrospective study of 89 patients. Eur J Nucl Med Mol Imaging 39:1416–1424
16. Byun BH, Kong CB, Park J et al (2013) Initial metabolic tumor volume measured by 18F-FDG
PET/CT can predict the outcome of osteosarcoma of the extremities. J Nucl Med
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emission tomography predicts outcome for Ewing sarcoma family of tumors. J Clin Oncol
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Cerebral Tumors
15
Alice Lorenzoni, Alessandra Alessi, and Flavio Crippa
Contents
15.1 Introduction ................................................................................................................... 301
15.2 Neuroimaging of Brain Tumor...................................................................................... 302
15.3 Advanced MRI Techniques ........................................................................................... 303
15.4 Nuclear Medicine Imaging ........................................................................................... 304
18
15.5 F-FDG PET ................................................................................................................ 305
15.6 Non-FDG PET-CT ........................................................................................................ 307
15.6.1 Amino Acid Transport and Protein Synthesis 308
15.6.2 Proliferation Rate 309
15.6.3 Somatostatin Receptor-Based PET 310
15.6.4 Membrane Biosynthesis 310
15.6.5 Oxygen Metabolism 311
15.7 Hybrid PET/MRI .......................................................................................................... 311
15.8 Brain PET/CT Techniques in Children ......................................................................... 312
References ................................................................................................................................ 313
15.1 Introduction
Pediatric brain tumors are the most common solid tumor in children (2500–3000
new diagnoses/year), accounting for approximately 20 % of all pediatric cancers.
They represent the primary cause of death in this patient population with a 5-year
survival of 60–70 %. The distribution of the central nervous system tumors is clas-
sified according to the anatomic compartment involved (see Table 15.1). Overall,
supratentorial and infratentorial tumors occur in equal frequency; supratentorial is
more common in children with age inferior to 2 years; infratentorial tumors are
more common between 4 and 10 years old. Brian tumors are classified
A. Lorenzoni (*) • A. Alessi • F. Crippa

Division of Nuclear Medicine, Fondazione IRCSS Istituto Nazionale Tumori, Milan, Italy
e-mail: alice.lorenzoni@istitutotumori.mi.it

DOI 10.1007/978-3-319-21371-2_15
302 A. Lorenzoni et al.
Table 15.1 Pediatric brain tumor classification

Infratentorial tumors Astrocytoma
Medulloblastoma
Ependymoma
Brainstem glioma
Supratentorial tumors
Intraparenchymal Astrocytoma
Ependymoma
Ganglioglioma/ganglioglioma
Desmoplastic neuroepithelial tumor (DIG)
Primitive neuroectodermal tumor (PNET)
Rhabdoid tumors
Atypical teratoid/rhabdoid tumors
Sellar/suprasellar Craniopharyngioma
Astrocytoma
Rathke cleft cyst
Germ cell tumors
Extra-axial Choroids plexus papilloma/carcinoma
Epidermoid/dermoid
Arachnoid cyst
histopathologically by cell type involved and graded for degree of malignancy by

mitotic activity, infiltration, and anaplasia. Management of these patients can be
challenging, as treatment is highly dependent on tumor histology, location, and
patient age. Selection of an appropriate therapy can only occur if the correct diag-
nosis is made and the stage of the disease is accurately determined. The location of
many tumors proximity to critical brain structures may preclude resection or make
difficult to perform diagnostic biopsy, which may be inaccurate in providing a cor-
rect diagnosis. Recurrence is not uncommon in childhood brain tumors; thus, long-
term management requires the coordinated efforts of a multidisciplinary team to
correctly identify and treat relapsed disease.
15.2 Neuroimaging of Brain Tumor
Neuroimaging plays a pivotal role as noninvasive tool for the evaluation of pediatric brain
tumors, from diagnosis to patient follow-up, allowing the planning of individualized
therapy and patient management. In recent years, attention has focused on imaging meth-
ods that examine specific tissue properties relevant to the tumor biology, with the aim to
elucidate unresolved clinical questions when using conventional structural imaging.
Clinicians expectations from neuroimaging concern the following critical points:
• Diagnosis and accurate localization of brain tumor and staging

• Definition of tumor borders, extent, and volume
15 Cerebral Tumors 303
• Grading
• Guide biopsy and treatment planning
• Evaluation of residual tumor after therapy; therapy monitoring
• Differentiation between tumor/radiation necrosis and tumor/inflammation
• Identification of recurrent tumor
Conventional imaging techniques routinely employed are magnetic resonance

(MR) and computed tomography (CT), which reveal morphological tumor features
(size and localization) and identify important secondary phenomena such as mass
effect, edema, hemorrhage, necrosis, and signs of increased intracranial pressure
[1]. MR imaging is the standard neuroimaging method for brain tumor evaluation.
Contrast-enhancing components on T1-weighted sequences reflect blood-brain bar-
rier disruption and identify malignant tumor region. Clinical routine MRI character-
izes brain tumors primarily by their appearance on T1-weighted images before and
after contrast enhancement and on T2-weighted images. Signal abnormalities in
T2-weighted/fluid-attenuated inversion recovery (FLAIR) images suggest nonen-
hancing tumor, perifocal edema, and treatment-related changes such as gliosis or
necrosis [2]. However conventional imaging techniques, which demonstrate impor-
tant structural information with a high sensitivity, have limited specificity, espe-
cially after previously applied radiation and/or chemotherapy. Furthermore they fail
to provide physiologic and functional information that is crucial for tumor grading,
predicting clinical outcome and response to therapy. Otherwise functional and
molecular imaging techniques may investigate on tumor cellularity and tissue ultra-
structure and tumor metabolism and vascularity, providing noninvasive assessment
of tumor biology thus improving the care planning process. These diagnostic tools
include magnetic resonance spectroscopy and positron emission tomography (PET)
performed with several radiopharmaceuticals. Challenges remain in determining
the optimum manner for incorporating these techniques into routine clinical prac-
tice, as part of a multimodal protocol.
15.3 Advanced MRI Techniques
Diffusion-weighted magnetic resonance imaging (DW-MRI) is an essential part of

MR imaging where T1- and T2-weighted images alone do not provide enough diag-
nostic information, examining tissue ultrastructure through measurement of the dif-
fusion properties of water [3]. High intensity on DWI indicates restriction of the
ability of water protons to diffuse extracellularly. In most tumors there is no
restricted diffusion, resulting in a normal, low signal on DWI. However, the peritu-
moral edema, which exhibits similar diffusion properties as tumor tissue, often pre-
cludes precise delineation of the tumor based on diffusion information alone.
Diffusion tensor imaging (DTI) is an advanced MR technique that describes the
movement of water molecules, useful to study microstructural differences among
different tumor types and grades. Indeed tumor type, the degree of invasiveness, and
growth rate can affect the diffusion properties [4]. Perfusion MR imaging can play
an important role in determining the malignancy grade of brain tumor. The perfu-
sion shows a better correlation with the grade of malignancy than the amount of
contrast enhancement [4]. MR spectroscopy (MRS) provides a measure of bio-
chemical changes due to the presence and concentration of various metabolites in
tumor that exhibits markedly different spectra from normal brain tissue [5, 6]. It has
been shown that brain tumors have decreased N-acetyl aspartate (NAA) signals
(neuronal/oligodendrocytic marker) and often also have increased levels of choline
(Cho) (increased membrane turnover, cellularity), leading to increased Cho/NAA
ratios. The decrease in NAA is interpreted as the loss, dysfunction, or displacement
of normal neuronal tissue. The “Cho” signal reflects the increased membrane turn-
over, correlating with the cellular density and the degree of tumor infiltration into
brain. The use of MRS to map Cho levels has therefore been suggested as a method
for defining tumor boundaries in treatment planning. Other metabolic changes are
elevated signals in the lactate and lipid region of the spectrum and also sometime
increased levels of myoinositol (mI), taurine (Tau), glutamine plus glutamate (Glx),
myoinositol plus glycine (mI 1 gly), and alanine (Ala) in short echo time (TE) spec-
tra. Taurine has been established as an important biomarker in distinguishing medul-
loblastomas (the most common posterior fossa neoplasm in children) from other
common pediatric brain tumors, such as cerebellar astrocytomas. MRS may provide
additional metabolic indices beyond anatomic information for tumor characteriza-
tion, especially when the differential diagnosis by neuroimaging is difficult, such as
in differentiating tumor from infection or radiation necrosis. While the utility of
MRS in diagnosis and evaluation of treatment response of brain tumors have been
widely documented, MRS has not been widely accepted as a routine clinical tool.
15.4 Nuclear Medicine Imaging
The role of nuclear medicine imaging is increasingly implemented in neuro-oncology,

especially if we consider the application in this field of molecular imaging with PET. In
fact it may provide important metabolic information of the tumor, promote the devel-
opment and application of individual treatment, and facilitate prognostic assessment
before and after therapy. Different molecular processes have been proposed to be use-
ful for brain tumor evaluation, like glucose metabolism, cell proliferation, membrane
biosynthesis, hypoxia, and neo-angiogenesis. The majority of PET radiopharmaceuti-
cals for the evaluation of brain tumor however deepen into increased intratumoral cell
proliferation since the evaluation of glucose metabolism in these diseases has impor-
tant limitations. The single emission tomography (SPET) with gamma emitters plays
a marginal and historical role in this setting. In 1990s studies of thallium-201 chlo-
ride (201Tl) SPECT in children with recurrent brain tumors had revealed that thallium
uptake is increased in pathological areas, but not in radionecrosis with a sensitivity
and specificity in tumor detection of 76.9 and 93.3 %, respectively [7]. Tl-avid tumors
comprised several histologic types, including astrocytomas/gliomas as well as medul-
loblastoma and ependymoma. Technetium-99 m hexamethyl-propylene-amine-oxime
(99mTc-HMPAO), a perfusion radiotracer, did not prove significant results, due to the
extreme variability of HMPAO distribution at the site of tissue abnormality.
Finally, 99mTc-sestamibi scans have been showed to be useful in differentiating

neoplastic brain tissue from normal parenchyma. Compared to 201Tl, it offers a bet-
ter definition of tumor margins and a higher contrast between tumor and background
with lower radiation exposure [8]. However, it shows an intense physiological
uptake in the choroid plexus of the ventricles, making the detection of lesions in the
paraventricular spaces difficult. A relationship between sestamibi uptake and tumor
grade was determined in astrocytoma. Brain SPECT with 99mTc tetrofosmin showed
comparable results to 99mTc-sestamibi scans [9].
18
15.5 F-FDG PET
The glucose analog 18F-FDG is the most frequently used radiopharmaceutical for
PET in oncological applications to evaluate the increased metabolic rate of glucose
in neoplastic cells. However, it also represents a common pathway of neurochemi-
cal activity in the brain providing approximately 95 % of the energy source and
being connected to neuronal activity. Consequently the physiological brain uptake
is very high in different brain areas, such as the cerebral cortex, the basal ganglia,
and the thalamus, which significantly limits the sensitivity for detection as well as
the specificity for delineation of adjacent neoplastic tissue. Furthermore not all
brain tumors are characterized by increase glucose metabolism, and the metabolic
status may vary significantly depending on tumor histopathological grade, prolif-
erative activity, and heterogeneous tissue component (necrosis, hemorrhagic/cystic
areas). Spence and colleagues [10] showed that 18F-FDG imaging 3–8 h after injec-
tion can improve the distinction between tumor and normal gray matter. 18F-FDG
uptake in low-grade tumors is usually similar to that in normal white matter, and
uptake in high-grade tumors can be less than or similar to that in normal gray matter,
thus decreasing the sensitivity of lesion detection [11–13]. The clinical role of
18
FDG PET in pediatric brain tumor is less firmly established compared to its value
in adult brain tumors. However, several studies indicate that FDG uptake plays an
important prognostic role reflecting malignancy grade and predicting survival. For
example, the demonstration of high uptake of FDG in a previously known low-
grade tumor suggests the diagnosis of anaplastic transformation. FDG PET may
assist stereotaxic biopsy improving the diagnostic yield of the procedure by detect-
ing metabolically active areas of tumor and identify the margins for tumor resection.
PET has been shown to be useful for the evaluation of children with brainstem glio-
mas. Hypermetabolic tumors are more likely to reflect a glioblastoma compared to
low or absent 18F-FDG uptake in anaplastic astrocytomas or low-grade astrocyto-
mas. Furthermore tumors with high FDG uptake are associated with a shorter sur-
vival time than tumors with absent or moderate FDG uptake. The optimal cutoff
levels for distinguishing low- from high-grade gliomas have been reported as 0.6 for
the tumor/cortex ratio and 1.5 for the tumor/white matter ratio with sensitivity and
specificity of 94 % and 77 %, respectively [14]. 18F-FDG PET may be useful in the
differential diagnosis between radiation necrosis and persistent/recurrent tumor.
The sensitivity ranges from 75 to 86 % and specificity from 40 to 94 % [15, 16].
Given these results, in up to one-third of the patients, inappropriate treatment would
be carried out. Co-registration with MRI may make FDG PET a more sensitive and
useful test in distinguishing recurrence from radionecrosis. Despite its recognized
limitations in brain tumor imaging, this imaging modality remains the most com-
monly used tracer nowadays (Figs. 15.1, 15.2, and 15.3).
Fig. 15.1 18F-FDG PET-CT in patient with right Gasserian ganglion tumor previously treated.
PET finding shows hypermetabolic uptake (blue circle) between the brain stem and the right sphe-
noid region, consistent with recurrence disease
Fig. 15.2 18F-FDG PET-CT performed in patient with anaplastic astrocytoma of the right tempo-
ral region surgically treated shows a faint FDG uptake in the posterior margin of the surgical cavity
(white arrow) consistent with recurrent/persistent disease
Fig. 15.3 Follow-up imaging in patient with previously left frontal glioblastoma. 18F-FDG
PET-CT (panel a) is negative for recurrent disease. 11C-MET PET-CT (panel b) shows abnormal
uptake in the left frontoparietal region suspicious for relapse
15.6 Non-FDG PET-CT
Non-FDG brain tumor PET radiopharmaceutical has been developed during the
past decades in order to improve the diagnostic sensitivity, specificity, and accuracy
of molecular imaging of brain tumors. Appropriate non-FDG tumor radiotracers
primarily concentrated on the increased proliferative activity of tumors cells. The
upregulation of protein synthesis explored by radiolabeled amino acids is an impor-
tant molecular target system for the evaluation of tumor growth as well as the DNA
synthesis explored by radiolabeled nucleotides and their precursors or the increased
of membrane synthesis. Of the radiotracers used for the aforementioned target sys-
tems, in brain tumor imaging, the use of 11C-L-methionine (MET) has been reported
most frequently, followed by 18F-fluoroethyl-l-tyrosine (FET), 11C-choline,
18
F-fluorothymidine (FLT), 11C-acetate, and 18F-fluoro-DOPA.
15.6.1 Amino Acid Transport and Protein Synthesis
Radiolabeled amino acids were introduced in 1982 as suitable PET tracers in brain
tumors [17]. The use of amino acids is based on an increased amino acid utilization
in cancer cells, which is known to play a pivotal role in cell proliferation, as well as
in extracellular matrix synthesis. For this purpose, a variety of radiolabeled amino
acids, like 11C-MET and aromatic amino acid analogs, like 18F-fluorotyrosine (18F-
TYR 18
), F-FET, 18F-fluoromethyltyrosine (18F-FMT), and 18F-DOPA, have been stud-
ied. Active amino acid transport is upregulated in the cell membranes of tumor
cells, regardless of the phase of the cell cycle, thus not representing a limiting
factor for successful PET imaging. High-contrast images can be acquired due to
high amino acid uptake in tumors and low uptake in normal brain tissue compared
to FDG. Possible problem may be caused by unspecific increase of amino acid
uptake due to damage of the blood-brain barrier [18]. Methionine uptake corre-
lates not only with cell proliferation but also with microvessel density, suggesting
the possibility of mapping tumor neovascularization. The accumulation of MET
in macrophage is irrelevant overcoming the limitation of FDG due to uptake in
inflammatory process. The uptake of 11C-MET gradually increased with age until
20 years especially in the frontal lobes and cerebellum, possibly reflecting high
activity of the neutral amino acid transporter and brain protein synthesis correlated
with brain metabolism. The highest uptake is found in the cerebellum and occipital
cortex, lower in the white matter [19]. The clinical application of 11C-MET has
been proved both for tumor diagnosis (tumor detection and characterization, extent
for treatment planning, biopsy guidance) and for treatment evaluation (therapy
monitoring, detection of recurrent/persistent disease). The specificity of MET for
brain tumor evaluation is generally high (85–100 %), and tumor/background radio
superior to 1.5 is considered indicative of tumor. The use of this radiopharmaceu-
tical is particularly interesting in suspicious low-grade glioma that cannot easily
identify with FDG PET. The MET uptake may be overlying among grades I and
II glioma and grades III and IV; however, it may provide a prognostic index in
patients with low-grade glioma [20]. Furthermore, 11C-MET is the radiopharma-
ceutical of choice for PET-guided biopsy. The distribution of MET in brain lesion
reflects the histological heterogeneity of the tumor, indicating more accurately the
areas to be biopsied [21]. It has been shown that MET-guided biopsy reduces the
number of attempts to obtained diagnostic samples, providing a more sensitive
mark compared to FDG. Another crucial point in the management of brain tumor
is the distinction between recurrence and post-therapy changes. The MET PET
has been shown to be superior to FDG (sensitivity 100 %, specificity 72 %, PPV
81 %, NPV 100 %) in differentiating viable tumor from radiation injury [22–24].
Infrequently a mild MET uptake may be observed due to the proliferation of glial
cell that may be present after radiation therapy. To increase the diagnostic perfor-
mance, it has been suggest that tumor-background ratio superior to 1.5–2 should be
considered indicative of tumor presence. 11C-methionine is probably the tracer of
choice at this time, in terms of its sensitivity, specificity, and accuracy, but its major
disadvantage is the short half-life of 11C (20 min) which implies on-site cyclo-
tron. 18F-amino acid has been shown comparable results, overcoming the problem
of radiopharmaceutical production [25]. 18F-fluoro-ethyl-tyrosine (18F-FET) is an

artificial amino acid taken up into upregulated tumoral cells but not incorporated
into proteins (contrary to natural amino acids such as 11C-methionine). 18F-FET
PET has excellent performance for the diagnosis of brain tumor and glioma in
the initial evaluation of newly diagnosed brain lesions. Initial comparison stud-
ies demonstrated that 18F-FET uptake ratios correlated with 11C-methionine uptake
but with a lesser uptake by inflammatory cells, allowing a better discrimination
between infectious and tumoral lesions or between tumor recurrence and radione-
crosis [26]. Among other applications, 18F-FET PET has shown value in the diagnosis
of brain tumor recurrence after initial surgery or radiotherapy and for directing
biopsy or radiosurgery. Furthermore early changes in 18F-FET uptake have been
suggested as a surrogate to predict tumor response to treatment and prognosis.
18
F-DOPA is also an amino acid analog which is taken up in normal brain by the
neutral amino acid transporter. The highest radiopharmaceutical uptake in tumor
and cerebellum generally occurred between 10 and 30 min after injection, while
the uptake in the striatum reaches the peak until 50 min after injection. 18F-FDOPA
has a sensitivity of 96 % and a specificity of 43 %, with an overall accuracy of
83 % for the detection of primary brain tumors [27]. Compared to FDG, 18F-DOPA
has shown a better accuracy with a higher sensitivity and a similar specificity,
allowing an excellent visualization of both high-grade and low-grade tumors. The
contrast between tumor and normal tissue is higher than that with 18F-FDG because
of the low 18F-DOPA uptake in normal brain tissue. Tripathi and colleagues [28]
in a series of 15 patients demonstrated that 18F-DOPA is superior both to FLT and
FDG for detection of primary and recurrent low-grade gliomas. 18F-DOPA should
demonstrate good feasibility in detecting local recurrence and residual tumor not
clearly seen on MR alone; however, the evaluation of this aspect is still limited in
literature.
15.6.2 Proliferation Rate
The assessment of cell proliferation rate and DNA replication by radiolabeled

nucleosides for PET image may be useful for the management of brain tumor in
order to evaluate treatment response or predict tumor progression. The thymidine
analog 18F-fluorothymidine (18F-FLT) has been developed and studied for this pur-
pose. Thymidine is rapidly transported into the cells and phosphorylated by the
enzyme thymidine kinase (TK)-1 to thymidine nucleotides, which are involved in
DNA replication, but not in RNA synthesis. Therefore, the uptake of 18F-FLT within
the cell provides a measure of cellular TK-1 activity [28]. The 18F-FLT accumulates
at low level in normal brain due to a lack of significant neuronal cell division, lead-
ing to an excellent contrast between tumor and background [29]. In gliomas, ele-
vated 18F-FLT uptake is associated with increased expression of antigen Ki-67, an
index of mitotic activity. The sensitivity of 18F-FLT for diagnosing brain tumor has
reported to be 83 %. The uptake of radiotracers in high- and low-grade tumors has
been shown to be significantly different [30]. However, the value of this tracer in
gliomas needs further evaluation in prospective studies.
15.6.3 Somatostatin Receptor-Based PET
Somatostatin is a neuropeptide produced by neurons and by various endocrine and

immune cells. The known functions of somatostatin include the regulation of most
endocrine and exocrine secretions; modulation of motor sensory, autonomic, and
cognitive functions; and inhibition of cell proliferation. The various functions of
somatostatin are mediated by a family of rhodopsin-like G protein-coupled recep-
tors (SSTRs), which comprise of five distinct subtypes: SSTR 1, 2A, 2B, 3, 4, and
5. Intracranial tumors like meningioma and glioma expressed different subtypes of
SSTRs. Among the gliomas, SSTR expression is commonly seen in low-grade gli-
oma but less frequently in high-grade glioma. Childhood brain tumors, especially
medulloblastoma and supratentorial primitive neuroectodermal tumors (PNETs),
show high SSTR expression, more frequently SSTRs 2 and 3. Scintigraphy with
111
In-DTPA-octreotide has been employed in medulloblastoma with success,
although studies are limited. More recently, Yüksel et al. [31] showed the utility of
SRS in recurrent or residual medulloblastoma, demonstrating that 111In-DTPA-octreotide
scintigraphy is more specific than MRI but less sensitive. A limited number of study
showed that 68Ga-DOTATOC PET is a promising PET tracer for imaging meningi-
oma, offering excellent imaging properties and a very high tumor-to-background
ratio also in small lesions [32, 33]. 68Ga-DOTA-peptide PET/CT may be a promis-
ing tool to investigate pediatric brain tumor known to express SSTRs; however, to
our knowledge, no literature is nowadays available concerning the utility of
68
Ga-DOTA-peptide PET/CT in medulloblastoma and PNETs.
15.6.4 Membrane Biosynthesis
Choline is a precursor for the biosynthesis of phosphatidylcholine and other phos-

pholipids, which are major components of cell membrane. Radiolabeled choline
(11C-choline, 18F-fluoromethylcholine, 18F-fluoroethylcholine) was demonstrated to
be rapidly cleared from blood within a few minutes and to show increased uptake in
different tumor entities. An excellent tumor uptake is present starting from 5 min
after injection with tumor-to-normal brain uptake ratios closed to 10. However, due
the decreased uptake in normal brain over time, the optimal contrast between tumor
and normal brain is reached at 20 min [34]. 18F-fluorocholine uptake correlates with
increasing tumor grade, and it was considered to distinguish high-grade gliomas and
benign lesions. In addition, increased peritumoral 18F-fluorocholine uptake was sug-
gested as a discriminating characteristic of high-grade gliomas. It has been shown
that radiolabeled choline accumulation is markedly elevated in anaplastic astrocy-
toma and glioblastoma multiforme [35]. Compared with other radiotracers tumor-
to-normal brain ratio of glioblastoma multiforme is much higher using
18
F-fluoroethylcholine than 18F-FDG or 11C-MET [36]. However, 11C-choline uptake
was reported to be extremely high in the choroid plexus, the venous sinuses, and the
pituitary gland, which limits its use for the delineation of tumor border in the prox-
imity of these structures. Therefore, amino acid tracers were supposed to be superior
for the evaluation of tumor extension, even if radiolabeled choline was suggested to
be useful in evaluating the potential malignancy of oligodendroglial tumors.
15.6.5 Oxygen Metabolism
Tumor hypoxia results from rapid tumor growth and concomitant insufficient blood
supply and is associated with tumor progression and resistance to radiotherapy.
Tumor hypoxia may also lead to necrosis, which is mandatory to establish the diag-
nosis in glioblastoma multiforme. Various endogenous markers of hypoxia are
found to be overexpressed in brain tumors. For example, in glioblastoma multi-
forme and in grade II and III astrocytomas, a heterogeneous pattern of the hypoxia-
inducible factor 1α (HIF-1α) overexpression was found in tumor areas adjacent to
necrosis [37]. The nitroimidazole derivatives 18F-fluoromisonidazole (18F-FMISO)
and 18F FAZA38 have been shown to be suitable to image tumor hypoxia by
increased uptake of these tracers since their metabolites are trapped exclusively in
hypoxic cells. 18F-FMISO uptake was observed in high-grade but not in low-grade
gliomas, and a significant relationship was found between 18F-FMISO uptake and
expression of vascular endothelial growth factor receptor-1 and antigen Ki-67 [38].
18F-FMISO PET images provide a spatial description of hypoxia in brain tumors
that is independent of BBB disruption. Generally, increased 18F-FMISO uptake is
found in the periphery but not in the center of a glioblastoma, since only viable cells
are able to accumulate the radiopharmaceutical. 18F-FMISO accumulated in both
hypo- and hyperperfused tumor regions, suggesting that hypoxia in glioblastoma
may occur independently of perfusion. Furthermore a correlation between FMISO
uptake and glioma grade was shown: low-grade gliomas did not demonstrated
hypoxia contrary on high-grade glioma (grade III and IV) [39]. The suboptimal
imaging properties (low target-to-background ratio as well as slow uptake in malig-
nant tissue) have limited the use of 18F-FMISO in routine clinical practice despite
the encouraging preliminary results. Nowadays only limited data investigating the
role of hypoxia in brain tumor in clinical settings are available.
15.7 Hybrid PET/MRI
PET and MR are the methods of choice for neuroimaging, allowing to combine the
metabolic information provided by PET imaging, with the various morphological
and functional parameters measured by MR. PET-CT has many limitations in neu-
roscience field since CT has limited soft tissue contrast and is therefore not suitable
for brain imaging. The integrated PET/MRI scanner technology is a recent develop-
ment that may have a significant impact on decision making of brain tumor.
Combined PET/MRI may improve the performance of PEt alone, combining high
resolution and excellent soft tissue contrast and molecular/functional behavior.
Reference MRI could help in delineating the area of interest, evaluating PET images
on the basis of MRI abnormalities as well. PET/MRI in comparison to PET/CT
reduces exposure to ionizing radiation eliminating the exposure to X-rays, which is

of particular interest in the imaging of younger patients. The effective dose of a
PET/MRI scan may be only about 20 % of the equivalent PET/CT scan [40]. A
study by Boss et al. [41] in ten patients with intracranial masses demonstrated that
tumor assessment with 11C-MET using PET/MRI was feasible with diagnostic
image quality compared to PET/CT. Bisdas and colleagues [42] demonstrated the
feasibility of simultaneous 11C-MET PET and MR spectroscopy for the evaluation
of tumor grading in patients with gliomas. Furthermore PET/MRI with 11C-MET
helped to delineate tumor margins and resection borders with higher accuracy than
singular use of MRI data in a series of four childhood patients. Various studies have
demonstrated the feasibility of simultaneous PET/MRI in many applications; how-
ever, further clinical studies and technical innovations are needed.
15.8 Brain PET/CT Techniques in Children
The preparation of children and parents for nuclear medicine imaging is an important
aspect of procedures. A thorough explanation of the scan should be given to the patient
and the parents an appropriate level of understanding, giving them time to ask ques-
tions or express concerns, particularly in presence of frightened or anxious children,
who may be less cooperative if they do not understand what is happening. A concise
patient history should also be taken at that time. To ensure an optimal position in the
scanner and to avoid movement artifacts, all patients should be comfortably immobi-
lized during study acquisition. Sedation or anesthesia is indicated when it is antici-
pated that simple methods will be inadequate to ensure acceptable immobility and the
protocols vary from institution to institution. In fact patient motion during the data
acquisition may result in image artifacts and render the study non-interpretable.
Ideally, intravenous access should be obtained outside the nuclear medicine depart-
ment to reduce stress for the child immediately before radiopharmaceutical injection
and thus to optimized the patient cooperation. The successful PET/CT examination in
children requires the establishment of acquisition protocols that allow high-quality
images with the minimization of radiation doses. The additional radiation exposure to
the pediatric patient from the CT component of the examination is an issue of concern.
CT is usually used for attenuation correction and anatomic localization only (very
low-dose CT; 25–35 mAs, pitch, 1.5) for the evaluation of the brain. Adequate attenu-
ation correction can be achieved with ultra-low-dose CT (80 kVp, 5 mAs, 1.5:1 pitch),
representing a 100-fold dose reduction relative to routine-dose diagnostic CT [43].
Patient preparation for 18F-FDG brains scans is similar to that for whole-body 18F-
FDG scanning. Administered activity is determined by patient weight (5.55 MBq/kg)
with minimum of 18 MBq and maximum of 370 MBq. The organ receiving the largest
radiation dose is the bladder (0.32 mGy per MBq). The acquisition 3D is performed
40–60 min after the intravenous administration of the radiopharmaceutical for 10 min
after the low-dose CT scan. If 2D acquisition is used, longer acquisition times are
required to achieve adequate count density. If sedation is necessary, it should be per-
formed as late as possible following administration of FDG. Images are reconstructed
Fig. 15.4 11C-MET images in patients with oligoastrocytoma surgically treated reveal the presence
of abnormal uptake in the anterosuperior margin of the surgical cavity. PET finding is consistent
with persistent disease
in the form of transaxial 128 × 128 or 256 × 256 matrix size. A final image resolution
may vary between 2.5 and 10 mm FWHM, depending on the resolution of the PET
system. Brain scans with 18F-DOPA are usually acquired 20 min after injection of
111–185 MBq of radiotracer lasting for about 30 min; PET/CT with 11C-MET
(6 MBq/kg) is acquired 20 min after injection (Fig. 15.4).
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Thyroid Cancer in Childhood
and Adolescence 16
Robert Howman-Giles and Christopher Cowell
Contents
16.2 Incidence, Genetic and Biological Behaviour 318
16.3 Initial Staging and Management 319
16.4 Imaging 319
16.5 Surgery 323
16.6 Radioiodine-131 Ablation and Therapy (RIT) 323
16.7 Pre-radioiodine Therapy Diagnostic Staging 123I/131I Whole-Body Scintigraphy 325
16.8 Risk-Adapted Management or Ongoing Risk Stratification 327
16.9 Recombinant Thyrotropin (rhTSH) Use for Diagnostic RAI WBS and Therapy 327
16.10 Paediatric Dose of RAI 328
16.11 Risks of RIT 329
16.11.1 Second Primary Malignancy (SPM) 329
16.11.2 Reproductive Issues 329
16.11.3 Pulmonary Fibrosis 330
16.11.4 Others 330
16.12 Practical Aspects 330
R. Howman-Giles, MB BS, MD, FRACP, FAANMS, DDU (*)

Departments of Nuclear Medicine, The Children’s Hospital at Westmead,
Sydney, NSW, Australia
Disciplines of Paediatrics and Child Health, Sydney Medical School, University of Sydney,
Discipline of Medical Imaging, Sydney Medical School, University of Sydney,
e-mail: r.howmangiles@sydney.edu.au
C. Cowell, MB, FRCP, FRACP
Departments of Endocrinology, Institute of Endocrinology and Diabetes, The Children’s
Hospital at Westmead, Sydney, NSW, Australia
Disciplines of Paediatrics and Child Health, Sydney Medical School, University of Sydney,
e-mail: chris.cowell@health.nsw.gov.au

DOI 10.1007/978-3-319-21371-2_16
318 R. Howman-Giles and C. Cowell
16.13 Thyroid Hormone Suppression 331

16.14 Follow-Up 331
16.14.1 Elevated Tg or Recurrence on RAI WBS 332
16.14.2 Elevated Tg But No Evidence of Disease on Diagnostic WBS 333
16.14.3 Management of Advanced DTC and Refractory Disease 333
Conclusion 333
References 334
16.1 Introduction
Differentiated thyroid cancer (DTC) in childhood is rare; however it is the most

common endocrine malignancy in children. DTC accounts for 1.4 % of all newly
diagnosed childhood malignancies and 7 % of childhood head and neck malignancy
and often presents with advanced disease and a higher rate of recurrence compared
to adults [8, 9, 14, 18, 25, 31]. Initial management recommendations are surgical
resection usually near total or total thyroidectomy followed by radioiodine therapy
(RIT), which results in favourable outcomes [25, 31, 34, 36]. Detailed reviews dis-
cussing incidence, clinical presentation, initial diagnosis, genetic aspects and surgi-
cal management have been recently published [11, 31, 33, 34, 38]. It should be
noted that the majority of papers regarding paediatric DTC are retrospective single
institutional reviews with only two being registry based [14].
16.2 Incidence, Genetic and Biological Behaviour
The incidence of paediatric DTC varies depending on interethnic and geographic varia-
tions. There is a significant difference in the genetic profiles and biological behaviour
between paediatric/adolescent patients and adults. When compared with adult DTC,
paediatric DTC has a larger tumour volume at presentation, more aggressive behaviour
with more frequent cervical lymph node involvement (42–90 %) and distant metastases
(7–20 %). The distant metastases are predominantly pulmonary, usually miliary in dis-
tribution and functional in biological behaviour. The tumour sodium iodine symporter
(NIS) expression is reduced compared to healthy thyroid cells but less often absent
which accounts for the higher percentage of paediatric patients with radioactive iodine
(RAI) uptake. Paediatric patients with DTC have a longer overall survival (>95 %) but
a higher recurrence rate (65–90 %) [14, 18, 25, 28, 31].
The most recent SEER data analysis by Hogan et al. based on the April 2008
release reviewed 1753 paediatric and adolescent patients with DTC to an age of
<19 years. The annual incidence was 0.54 per 100,000 patients, and the highest
incidence was seen in white adolescents aged between 15 and 19 years. Ninety five
percent were >10 years of age, and 74 % were between the ages of 15–19 years.
There was an annual increase in incidence of 1.1 % per year. The female to male
ratio was 4:1. The cancer histopathology was papillary (60 %), follicular variant of
papillary (23 %), follicular (9.5 %) and medullary (5 %) [14].
The genetic profiles of childhood and adult DTC show significant differences. RAS
mutations are rare in childhood (0–6.5 %) but seen in 12 % of adults with PTC, 29 %
in follicular TC and 50 % in anaplastic TC. RET/PTC rearrangements have a higher
prevalence in children (47–65 %) than adults (3–34 %). Patients with BRAF mutations
16 Thyroid Cancer in Childhood and Adolescence 319
(V600E) have a more aggressive course and have been described in up to 45 % of

adults with PTC. In children with PTC post Chernobyl disaster, RET rearrangements
were found in 41 % and BRAF in 12 %. RET and BRAF mutations did not coexist. In
sporadic DTC in children, BRAF (V600E) was found in 3–6 % of children [21, 31].
Medullary thyroid cancer is rare in the paediatric age group and often associated
with multiple endocrine neoplasia type II (MEN2) syndrome. It can occur sporadi-
cally or as familial MCT without other associated endocrine abnormalities [31] and
will not be discussed in this chapter.
16.3 Initial Staging and Management
Extensive presurgical staging is not usually undertaken for thyroid carcinoma. The
American Thyroid Association (ATA) guidelines advocate using the American Joint
Committee on Cancer (AJCC) and Union Internationale Contre le Cancer (UICC) clas-
sification systems. These staging methods relate to mortality and do not differentiate
between paediatric DTC and adult DTC, which usually behave differently. These sys-
tems have no significant role in paediatric DTC management. Rivkees et al. comment
that tumour size in a child with a smaller thyroid gland does not compare to an adult
with a larger gland. Also small tumours as seen in adults may be labelled as low risk,
which does not relate to paediatric patients. Adults with DTC are labelled low risk if
they do not have any of the following characteristics: (1) local or distant metastases; (2)
residual macroscopic tumour; (3) tumour invasion of loco-regional tissues or structures;
(4) aggressive histology such as tall cell, insular and columnar cell carcinoma, or vascu-
lar invasion; and (5) 131I uptake outside the cervical region. Most paediatric patients have
these characteristics and therefore are not low risk and require more aggressive manage-
ment [31]. Recent publications to determine a better indicator of the risk of recurrence
report the method of “ongoing risk stratification” or “delayed risk stratification”. This
allows a better determination of prognosis and ongoing management based on the
response to the initial treatment in particular RIT after thyroidectomy [3, 11, 39].
16.4 Imaging
Initially high-resolution ultrasound examination is recommended to diagnose solid thy-

roid nodules and to assess for extrathyroidal extension of disease and involvement of
neck lymph nodes, as the majority of childhood DTC will have metastatic cervical node
disease (Fig. 16.1). If indicated FNAB of the nodule and abnormal lymph nodes are
undertaken. Ultrasound is important prior to surgery to determine nodal involvement so
that these nodes can be surgically removed. In patients with advanced disease, determina-
tion of pulmonary metastases is essential. A non-contrast high-resolution pulmonary CT
will be helpful in diagnosing pulmonary metastases and in determining the prognosis and
assisting determination of RIT and the dose required. CT will assist in determining medi-
astinal involvement, which may be debulked during surgery. It should be noted that pul-
monary metastases may not be detected on chest x-ray (Fig. 16.1b) and CT scan and may
only be diagnosed after the ablative dose of 131I (Fig. 16.1c). MRI may also be useful with
regard examining neck nodes and mediastinal disease but is not routinely undertaken.
Radioiodine (RAI) whole-body scintigraphy (WBS) after near or total thyroidectomy
remains the most important staging procedure in DTC to detect residual thyroid tissue,
loco-regional disease, and distant metastases [11, 18, 28, 31] (Figs. 16.1 and 16.2).
Fig. 16.1 A 9-year-old female presented with a mass in L side of the neck. US (a): Mass L side isth-
mus: microcalcification, increased vascularity, and patchy heterogeneous echogenicity in remainder of
gland. Abnormal lymph nodes bilaterally consistent with metastatic disease. Chest X-ray (b) was nor-
mal. Pre-RIT 123I WBS (c) shows marked RAI uptake throughout both lung fields and significant resid-
ual thyroid tissue and loco-regional disease within the neck (a). Follow-up 123I whole-body scan at 6
months post surgery (b) shows a good response to RIT (6.3 GBq) but with persisting disease diffusely
throughout the lungs. She was treated with a further dose of 6.3 GBq 131I. Her Tg has fallen to 306 ug/L
from a baseline of 642 ug/L. Note reduced uptake in the left salivary glands due to sialadenitis
c a b

a b
Fig. 16.2 A 12-year-old male (weight 45 kg) presented with a dominant left thyroid nodule and
palpable bilateral neck lymphadenopathy. Post thyroidectomy and extensive bilateral neck and
mediastinal dissection, RAI therapy at a dose of 3.7 GBq was given. WBS shows extensive resid-
ual bilateral lymph node disease (a). At 6 months’ follow-up 123I WBS is normal (b). Tg after
withdrawal of T4 (TSH 109 mU/L) was 6.4 ug/L, and US of the neck was normal. SPECT/CT (c)
of the neck was performed and shows a focal increase consistent with recurrent disease in level II
on the left side. This was confirmed at surgery
16.5 Surgery
The optimal surgical management in paediatric/adolescent DTC follows the surgi-

cal recommendations in adult DTC. Due to the high incidence of multifocal disease
(42 %), loco-regional metastatic disease, distant metastases, and the higher recur-
rence rate in paediatric patients, near or total thyroidectomy is recommended [12,
25, 31, 34, 37]. Total thyroidectomy allows more accurate follow-up using serum
Tg and 123I/131I whole-body scans. Near or total thyroidectomy results in a signifi-
cantly lower recurrence rate in both adults and in children/adolescents. If nodal
metastases are diagnosed preoperatively with ultrasound or biopsy, selective lymph
node dissection is usually performed. Our institution and many other paediatric
centres recommend that central compartment neck dissection should also be under-
taken. This is particularly indicated if enlarged or abnormal nodes are detected by
palpation or ultrasound. The main argument against total thyroidectomy is the risk
of complications including hypoparathyroidism and laryngeal nerve damage.
However if surgery is performed by experienced thyroid surgeons with paediatric
expertise, there is no significant increase in complications [9, 12, 25, 31, 34, 37].
16.6 Radioiodine-131 Ablation and Therapy (RIT)
Surgery is usually followed by RIT, and this is a major therapeutic component of man-
agement in children and adults with DTC. The goal of the first RIT is for remnant abla-
tion which facilitates initial staging and detection of recurrent disease in follow-up (serum
Tg and 123I/131I WBS) and as adjuvant therapy with the aim of treating known residual
disease and destroying microscopic disease (Figs. 16.1 and 16.2). There are large retro-
spective studies confirming a decrease in loco-regional recurrence and reduced overall
specific mortality [6, 9, 30, 31, 39]. The National Thyroid Cancer Treatment Cooperative
Study group showed after near total thyroidectomy followed by RIT and suppressive
thyroid hormone (levothyroxine, LT4) therapy, there was significant improved overall sur-
vival in patients with NTCTCSG stage III and IV disease. There was some benefit in
stage II disease but no impact in stage I disease [19]. Guidelines published by the ATA
and the European Society for Medical Oncology agree in the use of RIT in high-risk adult
patients and state that RIT is not necessary in unifocal papillary thyroid microcarcinomas
(PTMC) without metastases, capsule invasion, and lack of aggressive histologies. In
adults, low-risk patients have an excellent prognosis with no proven benefit from RIT,
despite the risk stratification and methods used (AMES, MACIS). RIT may be recom-
mended in low-risk patients for more specific follow-up using serum Tg measurements.
RIT is also effective in the treatment of small residual tumours and metastases, which can
occur in microcarcinoma [6, 10, 27]. Nodal metastases have been described in approxi-
mately 38 % of PTMC [17, 26]. Middendorp and Grünwald recommend that RIT should
be undertaken routinely in DTC with few exceptions [24].
Even though the role of RIT in paediatric DTC continues to be controversial, the
majority of paediatric centres managing DTC recommend RIT in all paediatric
patients except possibly for stage I disease. RIT is strongly advocated by Chow
et al. in children with DTC. They recommend RIT in paediatric patients if any of the
following is present: tumour size >1 cm, cervical lymph node disease, extrathyroi-
dal extension, residual postoperative disease in situ or distant metastases.
Interestingly Chow et al. report only two children in their cohort with small <1 cm
cancers. Both of these had metastatic disease: one had cervical lymph node involve-
ment and the other pulmonary metastases. Local recurrence rates in children who
did not receive RIT have been reported to be significantly higher (42 %) compared
with children who received RIT (6 %). Pulmonary metastases developed in 20.8 %
of these patients who did not have distant metastases at presentation and had total
thyroidectomy but were not treated with RIT. A comparison cohort of 32 patients
who had been treated with RIT did not develop pulmonary metastases. Differences
were also found in outcomes for children treated between 1960 and 1986 compared
with those treated between 1986 and 1997. Total thyroidectomy was less often per-
formed prior to 1986 (67 % vs. 93.5 %), and these patients were less likely to
receive RIT (44.8 % vs. 0 %). Children treated prior to 1986 had a higher rate of
local recurrence (37.9 % vs. 3.2 %) and distant metastases (17.2 % vs. 0 %) [5].
Handkiewicz-Junak et al. reported 174 children treated with RIT after surgery.
Multivariate analysis showed that total thyroidectomy and adjuvant RAI treatment
independently decreased loco-regional recurrence risk. The overall consensus indi-
cates that RIT significantly reduces recurrence of thyroid carcinoma even though
this may take 20 or more years to occur [12, 28, 31]. A recent publication reported
the higher likelihood of recurrence related to younger age group, conservative surgi-
cal management, no RIT and multifocal cancer [25]. For successful ablation, serum
TSH must be elevated to >30 mU/L to achieve maximal RAI uptake. In children,
this usually occurs faster than in adults and takes between 2 and 3 weeks of LT4
withdrawal. Hung and Sarlis advocate using l-triiodothyronine (LT3) immediately
after surgery for 4 weeks and withdrawing this for a further 2 weeks prior to abla-
tion [15]. Some centres are increasingly using LT4 supplement post surgery fol-
lowed by recombinant human thyrotropin (rhTSH) stimulation for the RIT [23].
16.7 Pre-radioiodine Therapy Diagnostic Staging 123I/131I

Whole-Body Scintigraphy
Pre-radioiodine therapy imaging with diagnostic RAI WBS is recommended in pae-

diatric patients with DTC [5, 31]. At The Childrens’ Hospital at Westmead, Sydney,
pre-RIT diagnostic WBS is undertaken in the majority of patients using 123I WBS
with SPECT/CT (Figs. 16.2c and 16.3b). If 123I is not available, 131I diagnostic WBS
should be performed. The pre therapy WBS enables the evaluation of residual thy-
roid tissue and extent of loco-regional and/or metastatic disease, whether there
should be further completion surgery and determination of the appropriate RAI
dose. This information allows for more informed communication regarding
Fig. 16.3 A 12-year-old female presented with a

left-sided thyroid nodule. FNAB revealed
Bethesda V papillary carcinoma diffuse sclerosing
variant. The patient underwent total
thyroidectomy and central compartment node
dissection. The pre-RIT 123I WBS post surgery
showed active uptake in the midline of the neck
(a). SPECT/CT showed a faint increase in a level
II lymph node on the left side (MIP, coronal,
axial, co-registered) 123I scan (b). At 6 months’
follow-up, her 123I scan was normal (c). However
her Tg was elevated at 81.5 ug/L. Ultrasound was
normal. 18 F-FDG PET/CT (d) was performed
after withdrawal of T4, and this revealed multiple
focal areas of uptake in the left neck levels II and
II–IV and an area in the retrotracheal region
(co-registered PET/CT coronal view). Extensive
left neck dissection was performed and 15 nodes
were removed. Three nodes were positive for
thyroid carcinoma. Genetic testing revealed an
ALK mutation which indicates a more aggressive
disease
c d

prognosis, risk of recurrence and overall survival, including discussion of risks and
benefits relating to RAI therapy [36].
16.8 Risk-Adapted Management or Ongoing Risk

Stratification
The ATA in 2009 proposed a new classification for an estimate of recurrence of

disease by a classification of the probability of recurrence as low, intermediate or
high [6, 39]. Other parameters which are important for staging are available after
surgery and if RAI ablation or RIT has occurred. The variables include tumour his-
tology, evidence of vascular invasion, multifocal disease, involvement of regional
lymph nodes and any evidence of systemic metastases [3, 11, 39]. This risk-adapted
approach requires risk estimates that change over time based on response to therapy
and the course of the disease. Tuttle et al. reported 588 adult patients with DTC who
underwent total thyroidectomy and RIT who were stratified into low, intermediate
and high risk according to ATA categories. Persistent structural disease or recur-
rence was identified in 3 % of low-risk, 21 % of intermediate-risk and 68 % of high-
risk patients. Re-stratification in the first 2 years of follow-up reduced the likelihood
of finding persistent structural or recurrence in 2 % of low-risk, 2 % of intermediate-
risk and 14 % of high-risk disease. This demonstrated an excellent response to ther-
apy with Tg <1 ug/L without evidence of structural disease. Conversely an
incomplete response to initial therapy (suppressed Tg >1 ug/L, stimulated Tg
>10 ug/L), rising Tg or structural disease identified within the first 2 years increased
the likelihood of structural disease or recurrence in 13 % of low-risk, 41 % of
intermediate-risk and 79 % of high-risk disease [39]. This data has been confirmed
by Castagna et al. [3]. This method of risk stratification has not been reported in
paediatric DTC; however the data on overall survival and mortality related to DTC
in paediatric patients would suggest that this risk stratification estimation also
applies to paediatric and young adolescent patients.
16.9 Recombinant Thyrotropin (rhTSH) Use for Diagnostic

RAI WBS and Therapy
Thyroid hormone withdrawal may not be tolerated well. However most children and
adolescents usually raise their TSH more rapidly than adults after withdrawal of
LT4. Serum TSH may be elevated by using recombinant thyrotropin (rhTSH).
Patients are reported to feel better with rhTSH compared to the withdrawal method.
The radiation dose is approximately 30 % less [23, 28, 31]. Iorcansky et al. reported
in children and adolescents a comparison between withdrawal and rhTSH. TSH
levels after rhTSH stimulation (134 ± 75 mIU/L) were not significantly different to
TSH levels following withdrawal (188 ± 118 mIU/L) [16]. Luster et al. confirmed
this in a multicenter trial with the application of rhTSH in 100 DTC patients aged
between 4.9 and 18 years. Ninety-two percent of these patients received the adult
dose of 0.9 mg IM for 2 consecutive days and 34 % also combined with LT4 with-
drawal for <7 days. No clinical adverse events occurred in 88 % of the rhTSH
courses. Nausea (5 %) and vomiting (3 %) were the most common side effects. The
peak concentration of TSH was >25 mU/L in 98 % of cases [22]. A benefit of using
rhTSH in paediatric patients is the reduced radiation exposure; however, rhTSH is
not approved by drug regulatory agencies in the USA and Europe [31].
16.10 Paediatric Dose of RAI
There is no consensus on the appropriate dose of RAI for ablation and adjuvant
therapy in paediatric and adolescent patients. Studies in adults using 131I for remnant
ablation in low-risk patients have recommended doses at 30 mCi (1.11 GBq) and
compared this to higher doses of 100 mCi (3.7 GBq) both with withdrawal method
and using rhTSH. No significant differences in recurrence and outcome were found
[4]. In addition most centres recommend low-iodine diets for 1–2 weeks prior to
RAI treatment, and the patients should not receive iodinated contrast for imaging
studies.
Dose calculation of 131I is based on three methods: ablation, adjuvant therapy and
dosimetry. The empiric method in adults is based on fixed activities usually 100 mCi
(3.7 GBq) for ablation and neck loco-regional disease, 150 mCi (5.5 GBq) for pulmo-
nary metastases and 200 mCi (7.4 GBq) for bone and other metastases. The majority
of paediatric centres treating DTC in childhood and adolescence use the empiric
method, and currently, this is weight based or surface area adjusted to the adult dose
of 70 kg [15, 31]. Parisi and Mankoff suggest adult doses 100 mCi (3.7 GBq) for low-
risk patients, 150–175 mCi (5.5–6.5 GBq) for patients with loco-regional disease and
doses up to 200 mCi (7.4 GBq) for high-risk patients with large tumours, capsular
invasion, extrathyroidal spread, extensive nodal disease or distant metastases. The
dose is adjusted to weight, and some selected patients may have the dose based on
dosimetry [28]. Our institution follows this empiric method. Other factors that should
be taken into account are previous radiation therapy or if the patient has had cumula-
tive treatments with 131I and this is approaching 600 mCi (22.8 GBq) [15].
131
I activity based on dosimetry that is as high as safely administrable (AHASA)
showed that blood doses greater than 2 Gy, whole body retention of more than 120 mCi
at 48 h or 80 mCi retained by the lungs at 24 h were associated with bone marrow sup-
pression and lung fibrosis [2]. Recently, Verburg et al. reported AHASA levels for
children and recommended for treatment of distant metastases. Activities up to 5 mCi/
kg (200 MBq/kg) were found to be the highest safe limit. For initial ablation, even if
pulmonary metastases may be present, the authors state that at least 100 MBq/kg can
be administered safely [40]. Dosimetry allows dosing on patient tolerance; however the
techniques are very complex and time-consuming and take up to 4–5 days [20]. There
is no data in the literature indicating this method is better in regard to survival and
recurrence free survival than the empiric method of dose of RAI but may provide data
which could become helpful in the future to optimise the benefit-radiation risk ratio
particularly in patients with diffuse pulmonary metastases.
16.11 Risks of RIT
1. Second primary malignancy

2. Reproductive issues
3. Pulmonary fibrosis
4. Others
16.11.1 Second Primary Malignancy (SPM)
Initial studies of SEER database of 30,000 adults treated with RIT revealed no
effects of RIT on SPM risk. However recent review of this data suggests a small
carcinogenic effect with increased rates of haematological and solid SPM. An
increased risk of solid tumours and leukaemia was found with activities >200 mCi
(7.4 GBq) and 100 mCi (3.7 GBq). No effects were found with lower activities [31,
32]. Garsi et al. presented follow-up data on 11,007 European patients with
DTC. Patients >20 year of age had a risk of SPM of about 25 % higher than the
general population; however, the risk was not related to RIT for most patients but to
having DTC because the risk without RIT was also 25 %. This suggests a genetic
predisposition to SPM. An RAI-related risk of SPM was seen when the cumulative
dose of 131I was >200 mCi (7.4 GBq). Rubino et al. evaluated the European cohort
for patients < 20 years of age and found no evidence of increased risk of SPM after
treatment of DTC in children [31]. Sawka et al. reported a systematic review and
meta-analysis of the literature. The relative risk (RR) of SPMs in survivors who
were treated with RIT was increased with an RR of 1.19 compared to patients not
treated with RIT using a minimum latency period of 2–3 years after diagnosis. The
RR for leukaemia was increased at 2.5 %. The absolute risks were calculated at
approximately 1 % for SPM and 0.4 % for leukaemia. The authors concluded that
the risk of SPMs in thyroid cancer survivors treated with RIT is slightly increased
compared with those not treated with RIT [35]. Reiners et al. reported on outcomes
on 234 high-risk post Chernobyl cases of children and adolescents with DTC. The
median follow-up was 11.3 years. Distant metastases were found in 100 patients.
No haematological or solid malignancies were found [29]. Similar data was reported
by Michailovic et al. in a long-term follow-up of 51 paediatric patients with no
increased incidence of reproductive issues or SPM [25]. However as paediatric
patients and adolescents are younger when receiving RIT and have a much longer
life expectancy, it should be considered that there is an unknown but probable
increased risk of SPM in these patients.
16.11.2 Reproductive Issues
No excess malformations or cancer has been reported in offspring of patients treated

with an 131I activity of 100 mCi (3.7 GBq). Women treated with 100 mCi (3.7 GBq)
have an increased risk of miscarriage within 12 months of therapy. Pregnancy
should be avoided within 12 months of 131I therapy. In males, azoospermia and oli-
gospermia and increased FSH levels have been reported. This is usually transient
and dose dependent. There appear to be no long-term effects on fertility [25, 31].
16.11.3 Pulmonary Fibrosis
Pulmonary fibrosis may occur in patients with diffuse pulmonary metastases. In

general, RIT should not cause pulmonary fibrosis unless patients had an uptake of
80 mCi (2.96 GBq) or more in lung tissue [2] at 24 h. This level of activity is
unlikely to be achieved with conventional therapy. Reiners et al. in a review of RIT
in children and adolescents 25 years post Chernobyl disaster reported 69 patients
with pulmonary metastases. Seven showed persistent (n = 5) or transient (n = 2) evi-
dence of lung fibrosis on CT. These patients received cumulative 131I activities of
4.6–22.1 GBq. Four patients had received chemotherapy including bleomycin prior
to RIT. Five patients (7.2 %) developed advanced fibrosis. One patient in remission
for 17.5 years died from pulmonary fibrosis. This patient had received 5 courses of
RIT cumulative dose of 22.1 GBq within 16 months [29].
16.11.4 Others
Direct adverse effects from RIT can be early and late after RIT. Early side effects
include gastritis (nausea and vomiting), sialadenitis and haematological effects
(leuco-/thrombocytopenia). Neck pain from radiation thyroiditis is rare. The main
late side effect is xerostomia due to chronic sialadenitis, which may lead to loss of
taste and increased dental caries. The value of salivary stimulation with lemon and
lozenges is unclear [28, 31].
16.12 Practical Aspects
Management of DTC in children and young adolescents requires a multi-team

approach for initial management. Long-term care of children and adolescents with
thyroid cancer will require eventual transition from paediatric care to adult care.
This should be organised at the appropriate time, as long-term follow-up is required
for life. At The Children’s Hospital at Westmead, Sydney, the management team
includes personnel from endocrinology, surgery, nuclear medicine and nursing and
the radiation safety officer. Special requirements may occur with some patients par-
ticularly if they are mentally or physically handicapped. The use of RIT requires
extensive discussions with the patient and parents/carers. Issues which need to be
discussed include:
1. Stage of disease, risk of recurrence and risk of death.

2. Side effects from RAI both short term and long term including the risk of second
primary malignancy and risk to fertility.
3. Radioiodine dose ablation or adjuvant therapy and if dosimetry measurements

are required.
4. Method of administration: liquid or capsule. Younger children may have diffi-
culty swallowing a capsule.
5. Radiation issues: explanation for staff and parents as an inpatient and on
discharge.
6. Inpatient: practical aspects for being in an isolation room for 3 days. A parent/
carer room next to the therapy room is recommended. These rooms should be
linked by video and audio both ways. Entertainment for the patient, i.e. TV,
video and DVD, is suggested.
7. Discharge: precautions as for adult patients apply. Radiation safety issues may
arise if the mother is pregnant and there are young siblings living in the house.
8. Follow-up protocols: This depends on stage and response to treatment.
16.13 Thyroid Hormone Suppression
The majority of paediatric and adolescent patients will have surgery and RIT. The
patients will be then treated with levothyroxine (LT4) for hormone replacement and
suppression of TSH. In patients with high-risk disease, TSH suppression has been
reported to reduce the rate of recurrence and improve outcomes. TSH suppression
to a level <0.1 mU/L in intermediate- and high-risk adult patients is recommended
indefinitely, while biochemical or structural disease is present. If in remission, sup-
pression is recommended for a further 3–5 years. The level of suppression in low-
risk patients is debatable. In children, high levels of thyroid hormones and
suppression of TSH can have significant effects on growth and bone mineral density
and may also have an impact on behaviour and learning. However if disease is still
present, then suppressed levels of TSH are recommended. Consideration for modi-
fication of suppressive doses should be considered to reduce long-term complica-
tions. Baudin et al. recommend suppressing TSH to <0.1 mU/L and once in
remission to increase this to 0.5 mU/L. Compliance in children and adolescents may
be difficult, and Rivkees et al. state that TSH suppression cannot be considered a
mainstay of treatment in paediatric patients [1, 9, 31].
16.14 Follow-Up
Children and adolescents with DTC need long-term follow-up for life. The follow-
up protocols include periodic physical examination and surveillance laboratory
tests, i.e. serum TSH, Tg and Tg antibodies.
The standard for detecting disease recurrence is stimulated Tg either by with-
drawal or rhTSH stimulation. Depending on the initial stage of the disease, a
WBS after LT4 withdrawal or rhTSH stimulation using either 123I or 131I should be
performed at 6–12 months post initial management (Fig. 16.3). This study should
include SPECT/CT of the neck and thorax (Figs. 16.2c and 16.3b). Ultrasound of
the neck is recommended at this time, particularly if there was loco-regional
disease at presentation. FNAB is indicated if abnormal masses or lymph nodes are

detected. In abnormal lymph nodes, Tg should be measured in the node aspirate.
In cases with pulmonary metastases or distant metastatic disease, appropriate
imaging, i.e. non-contrast CT lungs and/or bone scintigraphy should be consid-
ered. Several recent publications recommend various pathways for follow-up [15,
31, 38].
Serum Tg is the most sensitive indicator for tumour recurrence after total thy-
roidectomy and thyroid ablation. Measurements of serum Tg antibodies are also
required as these can falsely lower serum Tg measurements. Tg antibodies and auto-
immune thyroiditis have been reported to occur in 20–80 % of paediatric patients. If
Tg antibodies are present, accurate determination of recurrence may be difficult.
Many Tg antibody-positive patients may convert to being TgAb negative after treat-
ment with surgery and RIT. However 44 % of patients may remain TgAb positive
for up to 5 years post ablation. Serum Tg while on LT4 replacement may miss small
amounts of residual tumour [23, 31, 36].
The frequency of follow-up should be tailored to each individual patient. This
is based on the stage, response of the disease to initial treatment and RIT. In our
institution, the majority of our patients have loco-regional disease. These patients
are evaluated at 6 months post thyroidectomy and RIT. They are then followed at
12 monthly intervals to 18 months. The investigations are serum TSH, Tg and Tg
antibodies and 123I WBS with SPECT/CT after withdrawal of LT4 or rhTSH stim-
ulation. In patients who are shown to be disease-free on serum Tg, WBS and
neck ultrasound, follow-up is yearly for another 2 years. If the patient remains
disease-free, the evaluation can be extended to 5 years. Once the patient has been
transitioned to adult care, the frequency of follow-up depends on the extent of
disease at presentation and whether there has been any recurrence of disease [31,
36, 38, 39].
16.14.1 Elevated Tg or Recurrence on RAI WBS
During follow-up, if the serum Tg remains or becomes elevated and/or the WBS
123 131
I/ I is abnormal, active DTC is still present or recurrence has occurred. The
initial imaging should be by ultrasound to determine loco-regional disease and
other imaging techniques, e.g. CT and MRI, depending on sites detected on
WBS. The management of persisting or recurrent DTC depends on whether this
is localised disease and/or metastatic disease. Localised disease in the neck
detected on ultrasound and or WBS should be confirmed by ultrasound-guided
FNAB. Tg estimation should be performed on aspirate of the mass or abnormal
lymph nodes [7]. Surgery could be considered if there is localised disease. RAI
therapy is recommended in most patients after surgery. If the persistent disease
is inoperable, then the patient can be treated with RIT alone. Multiple doses may
be required in patients with pulmonary metastases, and the patient may not
become disease-free. Often the pulmonary disease remains stable for many years
[28, 30, 31, 36].
16.14.2 Elevated Tg But No Evidence of Disease

on Diagnostic WBS
If there is elevated Tg but no other evidences of local or metastatic disease, refrac-

tory or recurrent disease that is not iodine avid is present. This may occur also if the
volume of disease is below the resolution of the WBS. This situation in paediatric
and adolescent patients in our experience is rare. The management in this situation
remains controversial. CT of the lungs and bone scintigraphy are often performed;
however, 18 F-FDG PET/CT is now recommended and has been shown to be sensi-
tive in 70–80 % of iodine-negative serum Tg-positive cases (Fig. 16.3). FDG PET
has been shown to indicate dedifferentiation of the malignant cells and to have
important treatment and prognostic implications. There is increased mortality asso-
ciated with FDG PET-positive disease. MRI should also be considered; if PET
imaging shows localised disease, this may be amenable to surgical clearance. In
adult centres, consideration of RIT empirically with 100–200 mCi (3.7–7.4 GBq) is
suggested. This is to determine any recurrence, which may be visualised on the
high-dose WBS and which may be amenable to surgery. This protocol has identified
disease in up to 50 % of cases with variable success. If this is negative, no further
RIT doses would be considered [6, 27, 31, 38].
16.14.3 Management of Advanced DTC and Refractory Disease
Advanced DTC is defined by the clinical characteristics. These usually are extrathy-
roidal invasion and distant metastases and refractory to RAI therapy or show no
significant uptake of radioiodine and are usually 18 F-FDG PET positive. It has
been reported to occur in 10–20 % of adult patients with DTC but is extremely rare
in the paediatric and young adolescent population. RAI therapy, suppression of
TSH and standard chemotherapy regimes are ineffective in these patients. However
recent data has shown some therapeutic effect in adults with DTC with targeted
therapies, in particular inhibitors of intracellular kinase signalling pathways [41].
Limited studies using tyrosine kinase inhibitors in adults with advanced DTC and
RAI resistant disease demonstrate that up to 25 % of patients benefit with improved
RAI uptake and partial disease remission. There is no data in children to date. There
also appear to be specific genetic and molecular biology characteristics in these
patients [13] (Fig. 16.3).
Conclusion
Thyroid cancer is rare in childhood and young adolescents with the majority
presenting with loco-regional metastatic disease, and the condition has a high
recurrence rate. There is good evidence that the optimal treatment, which lowers
the recurrence rate, is near or total thyroidectomy followed by radioiodine ther-
apy and TSH suppression while there is an active disease. Surgery has minimal
rates of complications if performed by high-volume thyroid surgeons experi-
enced in paediatric thyroid surgery. Follow-up should be at 6–12 months post
surgery with further doses of RAI if there is remaining residual thyroid or tumour
tissue and consideration of further surgery if focal tumour tissue is evident on
imaging. Repeat doses of RAI may be indicated for persistent or recurrent dis-
ease. For treatment of distant metastatic disease, dosimetry should be considered
to more accurately determine the maximum dose. TSH levels should be sup-
pressed while active disease is present, and long-term follow-up is essential as
recurrence can occur decades after initial diagnosis and treatment. It is important
that this disease is managed by physicians who are expert in this field. ATA
Guidelines for children with thyroid nodules and differentiated thyroid cancer
was published after this textbook was sent for publication [42].
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Other Neoplasms
17
Hossein Jadvar and Barry L. Shulkin
Contents
17.1 Hepatoblastoma............................................................................................................. 338
17.2 Desmoplastic Small-Round-Cell Tumor ....................................................................... 340
17.3 Langerhans Cell Histiocytosis ...................................................................................... 342
17.4 Adrenocortical Carcinoma ............................................................................................ 343
17.5 Summary ....................................................................................................................... 345
References ................................................................................................................................ 345
This chapter focuses on four relatively rare cancers in pediatrics. These neoplasms
include hepatoblastoma, desmoplastic small-round-cell tumor, Langerhans cell his-
tiocytosis, and adrenocortical carcinoma. We review the literature on the use of
scintigraphy and other correlative imaging in these cancers and present clinical case
examples for each condition.
Financial Disclosures: None

H. Jadvar, MD, PhD, MPH, MBA (*)
Department of Radiology, Keck School of Medicine of USC, University
of Southern California, 2250 Alcazar Street, CSC 102,
Los Angeles, CA 90033, USA
e-mail: jadvar@med.usc.edu
B.L. Shulkin, MD, MBA
Department of Radiological Sciences, St. Jude Children’s Research Hospital,
Memphis, TN, USA

DOI 10.1007/978-3-319-21371-2_17
338 H. Jadvar and B.L. Shulkin
17.1 Hepatoblastoma
Hepatoblastomas originate from immature liver precursor cells and may metas-
tasize, most often to bone and lungs. It is a rare malignancy in infants and chil-
dren, occurring in less than 1 % of childhood tumors with initial presentation that
is typically in the form of an abdominal mass [1–3]. An adult form of the disease
can also occur [4]. Alpha-fetoprotein (AFP) is often elevated although the phe-
notype with non-elevation of AFP can occur in which the prognosis is relatively
poor. Surgical resection is the mainstay of therapy for hepatoblastomas, often
following neoadjuvant and followed by adjuvant chemotherapy. Radiotherapy
may be considered if the surgical margin is positive for microscopic disease.
Transcatheter arterial chemoembolization (TACE) and photodynamic therapy
have also been employed for the local control of some hepatoblastomas [5, 6].
Liver transplantation is an option in appropriate clinical settings. Chemotherapy
with cisplatin as the main agent has been shown to improve outcome in patients
with hepatoblastoma [7].
Ultrasonography (US), computed tomography (CT), and magnetic resonance
imaging (MRI) are often used to detect and localize the liver mass [8]. 201-Tl
chloride has been shown to accumulate in hepatoblastoma [9]. Bone scintigraphy
may be used to assess for bone metastases, although the radiotracer may also
accumulate in liver tumors with calcification [10, 11]. Positron emission tomog-
raphy (PET) with 18F-fluorodeoxyglucose (FDG) has also been shown to be use-
ful for the imaging evaluation of the extent of the disease, restaging, and for
treatment response evaluation [12–14]. Cistaro et al. compared retrospectively
FDG PET/CT and the biological and radiological findings of nine patients sus-
pected with recurrent hepatoblastoma [15]. FDG PET/CT was found to be more
accurate than conventional imaging for assessment of patients with recurrent hep-
atoblastoma. However, in another retrospective study of 16 patients who under-
went FDG PET, three patients had false-positive results based on tissue sampling
analysis, and as such, the authors commented that positive results on FDG PET
should be considered with caution [16].
Potential utility of 18F-fluoromethyl choline PET/CT has also been explored
[17]. A group of investigators reported on the use of Tc99m-labeled monoclonal
anti-AFP Fab fragments in a single clinical case of hepatoblastoma [18].
17 Other Neoplasms 339
Clinical Case Example
Fig. 17.1 Three-year-old boy with hepatoblastoma. (a) Maximum-intensity projection image and
(b) axial images (from left to right: CT, FDG PET, fused FDG PET/CT) show irregular, heteroge-
neous, and markedly elevated uptake right lobe mass and less uptake in left lobe lesion
17.2 Desmoplastic Small-Round-Cell Tumor
Desmoplastic small-round-cell tumor (DSRCT) is a very rare embryonic neo-

plasm, primarily affecting adolescent males, that is, considered a type of soft tis-
sue sarcoma. It is aggressive with overall relatively poor prognosis. It often occurs
as an abdominal mass, but the disease may involve the peritoneum, pleura, lymph
nodes, bones, and other organs [19, 20]. The tumor is composed of small, undif-
ferentiated round or oval hyperchromatic cells with abundant desmoplastic
stroma, originated from a primitive pluripotent stem cell with multiphenotypic
differentiation and harboring karyotypic abnormality t(11;22) (p13;q12) [21, 22].
Treatment is multidisciplinary that may include debulking surgery, radiation,
myeloablative chemotherapy with stem cell rescue, and Y90 microspheres for tar-
geted treatment of liver lesions [23, 24].
Imaging plays a major role in localization and determination of the extent of
disease and for evaluating treatment response [25, 26]. Arora et al. evaluated the
imaging features of DSRCT in 62 patients [27]. The most common imaging find-
ing was multiple peritoneal soft tissue masses. Metastatic disease was docu-
mented in the liver, lungs, spleen, lymph nodes, and bones. FDG PET/CT
accurately detected 97.4 % of all lesions. FDG PET/CT has also been reported to
be useful in assessment of favorable chemotherapy response with significant
decline (by more than 50 %) in metabolic activity of lesions in comparison to
pretreatment activity level [28]. A single case report of the usefulness of FDG
PET in monitoring of treatment with a mammalian target of rapamycin inhibitor
has also been reported [29].
Fig. 17.2 Twenty-year-old woman with

DSCRT. Maximum-intensity projection image
shows extensive hypermetabolic soft tissue disease
involvement
17.3 Langerhans Cell Histiocytosis
Langerhans cell histiocytosis (LCH) is a group of clinically heterogeneous diseases

(ranging from indolent involvement of a single organ to a potentially fatal multisys-
tem disease) characterized by accumulation of Langerhans cells (a subtype of den-
dritic cells of histiocytic origin) of the immune system in various organs [30, 31].
The disease has previously been known as histiocytosis X, eosinophilic granuloma,
Letterer-Siwe disease, Hashimoto-Pritzker disease, and Hand-Schüller-Christian
syndrome [32]. The current designation of LCH was introduced in 1973 [33]. The
disease is now considered neoplastic given that it may be associated with the proto-
oncogene BRAF mutation. LCH is a rare clinically unpredictable disease in children
(about 3–5 cases per million children younger than 14 years) and can affect many
organs including the skin, bone, lymph nodes, liver, lung, spleen, and central ner-
vous system. Bone is the most common site of involvement in 78 % of patients
(skull > pelvis > femora > ribs). Skin and lymph node involvement may be present in
50 % and 30 % of patients, respectively [33]. Management of the disease remains
controversial but is generally risk adapted [34, 35]. Patients with disease involve-
ment of the skin, bone, and lymph node generally have relatively good prognosis.
However, patients with lesions in liver, spleen, lung, central nervous system, or bone
marrow are considered in high-risk group and have a worse overall prognosis [36].
Radiography and bone scintigraphy are often employed in the imaging assessment of
patients with LCH involvement of the bones [37–39]. Howarth et al. compared bone
scintigraphy and skeletal radiographic survey for detection of osseous lesions in 73
patients with LCH [40]. They reported sensitivity and specificity of 100 % and 61 % for
skeletal radiographic survey and 91 % and 55 % for bone scintigraphy, respectively.
Although fewer bone lesions may be detected on bone scintigraphy in comparison to
radiography, however, bone scintigraphy depicts those bone lesions that are metabolically
active [41]. Despite the utility of both bone radiography and scintigraphy, both these
scans are nonspecific and may not accurately portray the lesion response to treatment.
Whole-body MRI has also been employed and in one study was compared to radiogra-
phy and bone scintigraphy, demonstrating potential advantage of MRI over both these
imaging modalities in this clinical setting [42]. Few investigators have also reported that
somatostatin receptor scintigraphy with 111In-pentetreotide may be useful [43, 44].
PET-CT with FDG has been shown to be useful for identification of metabolically active
lesions, stratification of disease phases, treatment response monitoring and detection of
recurrence [45–49]. Kaste et al. evaluated the utility of FDG PET-CT in five patients with
LCH at various stages of treatment [50]. The metabolic information was found to be
significantly more useful than radiography or bone scintigraphy for assessing disease
extent and response to treatment. Mueller and colleagues compared FDG PET and MRI
scans in 15 patients with LCH with biopsy or follow-up scans serving as reference stan-
dard [51]. The sensitivity and specificity of PET were 67 % and 76 %, respectively. The
sensitivity and specificity of MRI were 81 % and 47 %, respectively. The authors con-
cluded that the imaging information provided by PET and MRI is complementary.
Fig. 17.3 Seven-month-

old female with anemia,
persistent fevers, and
several lytic bone
lesion-related
LCH. Maximum-intensity
projection images show
bone lesions in bilateral
humeri, a right lateral rib,
and bilateral femora
17.4 Adrenocortical Carcinoma
Adrenocortical carcinoma (ACC) is a rare malignancy with an estimated annual

incidence in the United States of approximately 1–2 per million (0.02 % of all can-
cers), a bimodal peak frequency in patients 5 years or younger and ages 30–50 years
and overall relatively poor 5-year survival of 20–45 % [52, 53]. A feature of ACC is
that it may be endocrinologically active and very aggressive clinically [54, 55].
Surgical resection of the tumor offers the best probability of potential cure.
The primary imaging modalities for initial assessment of ACC are CT and MRI
[56]. PET with FDG has also been found to be useful since most ACC tumors are
metabolically active [57–59]. In a recent study of 51 patients preoperatively, FDG
PET showed high sensitivity and specificity of 95 and 97 % for diagnosis of ACC
[60]. Leboulleux and colleagues showed that FDG PET/CT is more sensitive and
specific than CT for detection of metastatic disease, 90 % and 93 % for FDG PET/
CT and 88 % and 82 % for CT, respectively [61].
Despite the suggested diagnostic utility of FDG PET in ACC, other studies have
found that FDG PET may not be useful in the evaluation of the remaining adrenal
gland after treatment with mitotane and may not have prognostic utility [62].
Tessonnier et al. in a retrospective study of 37 patients with ACC found no correla-
tion between the primary tumor FDG uptake level and patient outcome as depicted
by overall survival and disease-free survival at 2 years [63].
Other PET tracers have also been examined in the imaging evaluation of patients
with ACC. 11C-metomidate was performed in 15 patients with adrenal mass and
showed the ability to discriminate the cortical from non-cortical lesions [64].
Metomidate binds to CYP11B enzymes of the adrenal cortex [65]. Kreissl and col-
leagues reported recently that the 123I-label of metomidate (123I-iodometomidate)
accumulates in both primary and metastatic lesions of ACC but with overall sensi-
tivity of 38 % (at a specificity of 100 %) [66]. Cytotoxic chemotherapy and mitotane
treatment did not affect tracer uptake in the lesions. Preclinical mouse studies of
radiolabeled Fab’2 fragment of the anti-adrenocortical Ac5 antibody has also been
reported [67].
Fig. 17.4 Fifteen-year-old girl with newly diagnosed adrenal mass and liver metastasis related to
ACC. (a) Axial images (from left to right: fat-saturated T2-weighted MRI, FDG PET, fused MRI,
and FDG PET/CT) show the primary adrenal tumor and (b) axial images (from left to right: CT,
FDG PET, fused FDG PET/CT) show the left hepatic lobe metastasis
17.5 Summary
We discussed the clinical demographics and the potential utility of scintigraphy

including PET in the imaging evaluation of four uncommon pediatric neoplasms,
hepatoblastoma, desmoplastic small-round-cell tumor, Langerhans cell histiocyto-
sis, and adrenocortical tumor. In general, PET appears to have a useful role in diag-
nostic and prognostic assessment of these rare tumors, although additional
prospective studies will be helpful to draw additional experience.
Acknowledgment National Cancer Institute, National Institutes of Health, grant R01-CA111613

(H. Jadvar)
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Diagnostic Imaging in European Eastern
Countries: a Russian Experience 18
L.S. Namazova-Baranova, A.A. Baranov, I.E. Smirnov,
A.V. Anikin, A.N. Getman, A.K. Gevorkyan, N.L. Komarova,
O.V. Kustova, O.V. Komarova, E.V. Komarova,
and E.V. Antonova
Contents
18.2 Nuclear Medicine (NM) 350
18.3 Nuclear Medicine at the Scientific Center of Children’s Health (SCCH) 352
18.4 Functional Radionuclide Kidney Examination 354
18.5 Radionuclide Hepatography 357
18.6 Radionuclide Cardiac Pathology Diagnosis 358
18.7 Radionuclide Pulmonary Pathology Diagnosis 363
18.8 Radionuclide Skeletal System Pathology Diagnosis 366
Conclusion 368
Suggested Reading 370
18.1 Introduction
Radiodiagnosis (diagnostic imaging using radiation sources) is one of the key types
of diagnosis in current pediatrics. We may trace the development trajectories of how
imaging technologies have changed since Wilhelm Conrad Roentgen discovered
X-rays only 120 years ago. One of them has consisted in development of external
ionizing radiation imaging methods – from plain radiography to high-resolution
computed tomography, the second – in introduction of the methods involving exter-
nal radiation sources not based on the gamma radiation (ultrasonography, MRI). All
pediatricians know that the US is safe, highly available, and diagnostically valuable.
Thanks to high natural tissue contrast and absence of radiation exposure, MRI may
L.S. Namazova-Baranova (*) • A.A. Baranov • I.E. Smirnov • A.V. Anikin

A.N. Getman • A.K. Gevorkyan • N.L. Komarova • O.V. Kustova
O.V. Komarova • E.V. Komarova • E.V. Antonova
Scientific Center of Children’s Health, Moscow, Russia
e-mail: namazova@nczd.ru

DOI 10.1007/978-3-319-21371-2_18
350 L.S. Namazova-Baranova et al.
be successfully used even in the youngest children. Finally, the third trajectory con-
sisted in development of the internal radiation source (radionuclides) methods: from
gamma-ray chambers to the state-of-the-art positron emission tomography (PET)
methods.
Nowadays, large medical centers are equipped with all the high-technology diag-
nostic systems – from expert US apparatus to modern CT and MR tomographs, as
well as modern gamma-ray systems. The amount of data such equipment is capable
of providing is extremely large. However, it is difficult for pediatricians to orient
themselves in this data glut. Each method features individual advantages and disad-
vantages, aims and objectives, spheres of application, and possibilities and con-
straints. We obtain the maximum amount of diagnostic data only when we are able
to use a set of methods including any of the methods and compare results. The
economic aspect of the issue ought not to be ignored either, which is why ways of
optimizing examinations consisting in cost reduction remain top priority.
Whereas rapid development of imaging technologies in the end of the twentieth
century and in the beginning of the twenty-first century resulted in higher demand
for radiodiagnostic methods using expert equipment (ultrasound systems, digital
radiographic systems, CT and MR tomographs) in clinical pediatrics, examinations
using radiopharmaceuticals (RPs) remain less common and widely known. Not
only patients, but also physicians mystify them. At the same time, these are unique
technologies, which help to directly assess condition of the body on the cellular
level. The set of these methods is known as nuclear medicine and molecular imag-
ing (real-time imaging of processes on the molecular level).
18.2 Nuclear Medicine (NM)
This term has two definitions – a conventional one and a modern one. According to
the initial definition, nuclear medicine is a branch of clinical medicine specializing
in the use of radionuclide pharmaceuticals for diagnosis and treatment, i.e., the NM
method is based not on the externally induced (as in radiographic methods, such as
CT or MRI), but on the body-derived radio emission.
According to a more modern and wider definition, NM is a branch of high-
technology medicine using radionuclides and other radiation (both ionizing and
non-ionizing) sources to treat and diagnose diseases, such as:
1. Radionuclide and other diagnostic methods, including:

(a) Single-photon emission computed tomography (SPECT)
(b) Positron emission tomography (PET)
(c) Non-radionuclide tomographic methods:
(i) Computed tomography (CT)
(ii) Magnetic resonance imaging (MRI)
2. Radionuclide and radiation therapy (RT)
3. Radiopharmaceutical (RP) manufacturing technologies
4. Use of charged particle accelerators for generating isotopes and performing radi-
ation therapy
18 Diagnostic Imaging in European Eastern Countries: a Russian Experience 351
5. Computer technologies of obtaining and storing tomographic images, as well as

of planning radiation therapy and other calculations
It ought to be mentioned that information technologies as a set of methods of

obtaining, processing, transforming, transferring, and providing data are ingrained in
all spheres of nuclear medicine. In tomography, complex software suites are used to
obtain images; they obtain information from the tomograph and recover and transform
the image to make it more comprehensible for physicians on the screen (Fig. 18.1).
Nuclear medicine has become ingrained into the arsenal of diagnostic means of
modern pediatric establishments. Its distinctive feature is functionality of radionu-
clide methods. Although gamma-ray images do not feature such a high space reso-
lution as CT or MRI images, they are capable of reflecting pathophysiological and
metabolic alterations occurring within the body by means of volume RP distribution
in the body, as RPs concentrate in certain organs and form hyperfixation foci.
The number of radionuclide examinations (conventional NM) has been doubling
every 3–5 years in the developed countries in the recent years; it is now ca. 10 per
1000 persons. Despite intensive development of other instrumental diagnostic
methods, this level has not decreased yet due to the fact that radioisotope diagnosis
is primarily a functional and biochemical examination and helps to detect many
diseases at such early stages when other methods are insufficiently informative.
MRI
CT
SPECT
Fig. 18.1 Comparison of magnetic resonance and computed and SPECT tomography images
SPECT KT SPECT/KT
Fig. 18.2 Comparison of SPECT and CT images and a hybrid SPECT/CT image, which helps
to determine topography of the pathological focus
Nuclear medicine has been being especially dynamically developed since 1963,
when H.O. Anger invented a gamma-ray chamber – a fundamentally new device
designed to obtain gamma-ray images, which is based on the use of radionuclide ion-
izing radiation. The principal design principle of gamma-ray chambers (large flat scin-
tillation crystal with photomultipliers above it) makes the device capable of 3 types of
radionuclide examinations: radiometry, radiography, and imaging. Gamma-ray cham-
bers ensure immediate registration of the in vivo administered RP radiation without
moving a detector over the patient, high space resolution, and radiation registration rate.
Radionuclide imaging (scintigraphy) includes several methods of obtaining images
reflecting distribution of labeled compounds within the body. These substances – radio-
pharmaceuticals (RPs) – are intended to observe and assess visceral physiological func-
tions. According to a range of authors, one of the possibilities of nuclear medicine is
creation of body metabolite-based RPs; use of such RPs will provide radionuclide diag-
nosis with a way to map functional processes and the change rates thereof occurring in
a patient’s body similar to metabolic pathway maps. In this case RP fixation will dem-
onstrate viability and functional activity of the tissue or organ under analysis.
There are more than 100 radionuclides used to produce RPs for nuclear medi-
cine. However, only technetium-99 m (99mTc), iodine-123 (123I), as well as thallium
(201 T1 and 199 T1) and gallium (67Ga citrate) nuclides have maintained practical
value for radionuclide diagnosis, as their physiochemical and biological properties
make them optimal to perform single-photon gamma-ray examinations in children.
Combined SPECT/CT and PET/CT systems have been becoming common in
pediatrics in recent years. For example, modern gamma-ray chamber Discovery
NM/CT 670 is a combined SPECT/CT system integrated into a single gentry and
capable of producing a high-quality combined image of functional and morphologi-
cal patterns (Fig. 18.2).
18.3 Nuclear Medicine at the Scientific Center of Children’s

Health (SCCH)
At the moment, the Center has 5 MR tomographs (10.35 T tomograph, 31.5 T

tomographs, and 13 T tomograph), 3 multispiral CTs (160–320 slices), more than
20 expert US systems, a digital mammography system (1 MRI of 0.35 T, 3 MRI
- of 1.5 T, 1 MRI - of 3 T), 3 bone densitometers, 5 digital radiodiagnostic systems,

and 2 digital angiographs.
The principal technical means of radionuclide diagnosis at the SCCH is expert
integrated gamma-ray chamber Millennium MG (USA). In package with a special-
ized computer system (workstation Xeleris 3) (GE Healthcare, USA), the gamma-
ray chamber helps to perform all types of in vivo radionuclide examinations using
the standard integrated processes for different data accumulation modes. The exam-
inations performed with such devices are known as single-photon emission com-
puted tomography (SPECT). Whereas X-ray (transmission) tomography is based on
obtaining computerized images of body “slices” after processing information on
X-ray (external) radiation absorption by tissues, SPECT helps to visualize distribu-
tion of the RP administered to the examination subject in the form of two-
dimensional planes.
In order to produce RPs we use nuclide generators intended to produce radionu-
clide pharmaceuticals numerous times directly at the site by means of separating
genetically related – parent and daughter – radionuclides. The latter usually has a
shorter half-life and is being continuously generated from the parent one. Generators
are convenient as the personnel may transport them and subsequently separate the
daughter nuclide ex tempore directly at a diagnostic laboratory. The most common
radionuclide in pediatrics is technetium-99 m (99mTc) as it has the scintigraphy-perfect
monoenergetic gamma radiation spectrum. Use of short-living 99mTc with half-life of
6 h and soft γ-radiation of 140 keV makes the diagnostic procedure radiologically
safe, as it reduces the pediatric patient’s radiation exposure tens of times.
We use GT-2 M generators 99mTc activity of 5.5 GBq on the day of delivery,
which ensure generation of an eluate featuring high and stable output of techne-
tium-99 m throughout the lifetime. This nuclide is convenient for clinical use, as it
easily forms complexes with the compounds tropic to tissues of various organs. We
also use special commercially available vialed lyophilisate sets for clinical practice:
technefor (technetium oxabifor), technephyte (technetium phytate), technetril
(technetium sestamibi), technemek (technetium succimer), technemag, pentatech
(calcium trisodium pentetate), bromezida (mebrofenin) etc. 99mTc-based RP
compounding usually consists in simple concoction of a lyophilisate and the eluate,
although specific manipulations may sometimes be required.
The specific apparatus present the obtained data on the dynamics of physiologi-
cal processes as follows:
• In the quantitative form – number of pulses (scintillations) per image pixel

• In the graphic form – activity/time graphs (radiograms)
• In the form of images (imaging)
According to our data, radionuclide diagnosis is the most informative and cost-
effective method of functional examination of various organs with high specificity
and sensitivity in pediatrics. Analysis of diagnostic gamma-ray chamber examina-
tions demonstrated that 46 % there of have been scintigraphic examinations of
kidneys and urinary organs, 19 % of the liver, 17 % of the heart, 14 % of the lungs,
2.6 % of the skeletal system, and 1.4 % of the thyroid gland and testicles.
18.4 Functional Radionuclide Kidney Examination
Functional radionuclide kidney examination-renograthy which is based on registra-

tion of the intravenously administered RP – 99mTc technemek (DMSA) with activity
of 80–600 MBq, which is selectively captured and excreted from kidneys – gamma
radiation over kidneys.
Depending on the indication, we take a single image (static mode) or series of
consecutive images at different points in time (dynamic mode). Static nephroscin-
tigraphy is used to measure shape, dimensions, and volume of kidneys as well as to
determine RP distribution, specific activity, and integral capture index. Dynamic
scintigraphy shows activity in the renal microcirculation (perfusion) directly after
RP administration, transfer thereof to renal tubules (glomerular filtration) after that,
and gradual activity decrease due to urine runoff in the end, which is why it is used
to determine the following parameters in children: functional RP distribution
(“interest zones”), activity/time curves (renograms), and 2-min capture (indicator of
the functioning tissue amount).
Along with that, we have proposed a method of measuring the amount of RP
captured by each kidney and both kidneys in tote (RF patent No. 2392968), which
helps to rapidly detect the renal functioning tissue amount (FTA) changes in patients
with various forms of renal pathologies. This method helps to reduce duration of
examination, as the renal FTA measurement requires lower (3.2 times) radiation
exposure of the patient and does not require interruption of gamma-ray image
recording or radioactive decay correction.
A healthy child’s renogram consists of three characteristic segments: segment 1
(vascular), initial steep curve upturn for 40–50 s considered to be a consequence of
RP entry into the kidney’s vascular system; segment 2 (secretory), subsequent less
steep upturn for 3–5 min reflecting RP passage to kidney cavities via tubules; it
finishes with the highest curve peak indicating the maximum drug accumulation
period (Tmax); after that technemek is gradually excreted to the urinary bladder;
hence, segment 3 (excretory) is represented by a steep curve downturn due to RP
excretion from the kidney. Excretory segment’s duration is calculated on the basis
of the drug’s half-life – T1/2 (normally, up to 12–15 min). The following pathological
types of renograms are distinguished depending on the form of renal pathology:
obstructive (urinary tract obstruction), parenchymatous (decelerated secretory and
excretory renal function in the event of chronic pyelonephritis, hydronephrosis,
etc.), isosthenuric (acute secretory and excretory renal malfunction in the event of
glomerulonephritis and arteriosclerotic kidney), and afunctional (in the absence of
secretory-excretory renal function) (Fig. 18.3).
Examination of children with vesicoureteral reflux (VUR) of different severity
detected unilateral and bilateral lesions in 52.6 % and 47.3 % of the cases, respec-
tively. Static nephroscintigraphy helped to detect kidney injuries of different
severity in all the examined patients with VUR. A twofold decrease in the affected
kidney’s functioning parenchyma amount was observed in patients with stage III
VUR or worse. The established regularities indicate that the primary factors of the
a b
Fig. 18.3 (a) Patient S., 14 years of age. Nephroscintigraphy. “Interest zones” in the area of renal
parenchyma and pelves, as well as of the urinary bladder. Renogram changes: normal cortical
transport, moderately decelerated excretion from the left pelvis, reflux. (b) Patient O., 15 years of
age. Nephroscintigraphy. Extremely acute depression of the right kidney’s function, urodynamic
disorders, and CRF
Fig. 18.4 Patient R., 6 years of age. Dynamic nephroscintigraphy 6 months after operative cor-
rection of bilateral megaloureter: front view (left), back view (right). Right kidney’s volume
(43 cm3) is lower than normal (75 cm3). Right kidney’s clearance recovery
functional condition of kidneys include not only the reflux grade, but also the
nephrosclerosis type or the combination thereof, especially in the event of bilat-
eral VUR in children characterized by significant impairment of the structural-
functional condition of kidneys. Nephroscintigraphy also helps to adequately
assess reserves of the functionally active renal parenchyma in children with VUR
(Fig. 18.4).
Radionuclide examinations of 2–16-year-old patients with hydronephrosis of

different severity showed that the primary factors of the kidney’s functional mal-
function include not only the obstruction severity and nephrosclerosis grade, but
also the residual functioning tissue amount (FTA) of kidneys, which is quantita-
tively measured in the process of nephroscintigraphy; this helps to assess functional
reserves of the renal parenchyma in such patients and prognosticate the disease
course (Fig. 18.5).
Thus, use of nephroscintigraphy helps to significantly speed the pediatric
patient’s examination up, accurately measure the functionally active renal paren-
chyma amount present at various pathological forms in children regardless of age,
significantly optimize outcome prognosis, and reduce risk of chronic renal failure.
Fig. 18.5 Patient A., 11 years of age. Hydronephrosis of the only – right – kidney. Condition after
left-sided nephrectomy. Gamma-ray images – significant decrease in the functioning tissue
amount, low secretory-excretory function, urodynamic disorders. Risk group patient
18.5 Radionuclide Hepatography
Radionuclide hepatography using 99mTc technephyte (37–150 MBq) is an organ-

specific method of examining absorption-excretory function of hepatocytes and
biliary tract patency. Dynamic 1–1.5-h-long examination of liver helps to detect the
slightest deviations in the hepatocyte function, specify the type of jaundice, distin-
guish between active and non-active forms of hepatitis, and determine prognosis of
the disease (Figs. 18.6, 18.7, and 18.8).
It ought to be mentioned that quantitative analysis of activity/time curves of
the “interest zones” obtained by means of hepatobiliary scintigraphy helps to
comprehensively assess concentration and motor function of the gallbladder,
determine occurrence of bile reflux to stomach and patency of biliary tracts,
detect incompetence of the sphincter of Oddi or the sphincter of Lutkens, spec-
ify occurrence of cholestasis, and qualify morphological condition of the liver
Fig. 18.6 Patient L., 10 years of age. Hepatoscintigraphy: chronic hepatitis. Liver enlargement,
uneven colloid distribution, marked splenomegaly, spleen RP accumulation exceeds the norm by
15 %. Below: the same patient (L., 10 years of age): axial computed tomograms (right) and frontal
image reconstruction (left). Chronic hepatitis. Diffuse liver enlargement, normal shape, sharp and
smooth contours. Marked splenomegaly
Fig. 18.7 Patient K., 13 years of age. Hepatoscintigraphy: developed hepatic cirrhosis, altered
shape of the organ, markedly uneven (spotty) RP distribution, splenomegaly, high spleen RP accu-
mulation. Below: the same patient (K., 13 years of age): axial computed tomograms (right) and
frontal image reconstruction (left). Hepatic cirrhosis, segmental liver contours, liver enlargement.
Uneven structure with multiple regenerative nodes. Cobblestone appearance. Leveled hepatic vas-
cular pattern. Splenomegaly
and the gallbladder, as well as of extrahepatic bile ducts (internally). Along with
that, CT and scintigraphy complement each either at some forms of hepatic
pathologies and ensure excellent diagnostic effect (Figs. 18.9, 18.10, 18.11, and
18.12).
18.6 Radionuclide Cardiac Pathology Diagnosis
Radionuclide cardiac pathology diagnosis in children consists in perfusion myocar-

dial scintigraphy by means of selective 99mTc technetril set (250–550 MBq) accumu-
lation in the myocardium. It involves measurement of the left ventricular (LV)
end-systolic and end-diastolic volume, as well as ejection fraction, determination of
the LV wall’s hypo- or dyskinesia zones, assessment of the LV walls’ motility and
Fig. 18.8 Patient M., 11 years of age. Hepatoscintigraphy at a focal liver lesion: developed hyda-
tid of the right hepatic lobe: altered colloid distribution and shape of the organ, significant singular
RP accumulation defect in the form of a “cold” focus with sharp contours. Below: the same patient
(M., 11 years of age): axial computed tomograms (right) and frontal image reconstruction (left):
hydatid of the right hepatic lobe, slight liver enlargement. Large unicameral cyst with thickened
conspicuous capsule and internal content with linear barriers in the parenchyma of liver segments
IV and VIII. No symptoms of capsule calcination
the systolic/diastolic ratio and three-dimensional analysis of tomographic heart

slices, as well as analysis of the perfusion map and volume/time curves. The exami-
nation may also involve radiocardiography (RCG) based on the curve recording of
the radiotracer’s blood circulation parameters.
It is also important to mention that, unlike other methods, radionuclide diagnosis
allows directly examining a heart under stress (physical or psychological) and prog-
nosticating the result of such a stress exposure, i.e., the patient’s or the young sports-
man’s possible future (Fig. 18.13).
Perfusion myocardial scintigraphy holds a special place in diagnosing various
forms of cardiomyopathies in children; this process requires analyzing the perfusion
map and volume/time curves (Fig. 18.14).
Fig. 18.9 Patient M., 10

years of age. Frontal liver
intravenous contrast-
enhanced computed
tomography: chronic
Budd-Chiari syndrome.
Compensated ischemic
hepatic cirrhosis.
Significant disproportion
of liver segments, marked
caudate lobe enlargement.
Thinned branches of the
hepatic artery and the
portal vein, smaller amount
and order thereof
Fig. 18.10 The same

patient (M., 10 years of
age). Axial liver
intravenous contrast-
enhanced computed
tomography: diffuse focal
hepatic parenchyma
alterations, calcificates.
High occlusion of hepatic
veins (visualized in the
ostial projection).
Deformed and narrowed
lumen of the liver segment
of the inferior vena cava
Fig. 18.11 Patient M., 10

years of age. Chronic
Budd-Chiari syndrome.
Static hepatoscintigraphy
(99mTc technephyte) –
07.06.2013. Frontal
projection. Large RP
accumulation defects with
sharp contours (tissue
necrosis foci). Significant
size reduction of the right
lobe, enlargement of the left
lobe
Fig. 18.12 The same

patient (M., 10 years of
age). Static
hepatoscintigraphy (99mTc
technephyte) – 07.06.2013.
Posterior projection. Large
RP accumulation defects
with sharp contours (tissue
necrosis foci). Significant
size reduction of the right
and portal lobe, significant
enlargement of the left
lobe
a b
Fig. 18.13 (a) Tomographic heart slices obtained with ECG-synchronized perfusion SPECT for
visual assessment of the left ventricular myocardium in three projections (examination of sports-
man S., 16 years of age). (b) Tomographic heart slices (examination of sportsman S., 16 years of
age) obtained at the stress test peak: temporary RP accumulation defect in the left ventricular
inferior wall (hypoperfusion zone) at physical stress (shown with arrows); no defect at rest
a b c
Fig. 18.14 Patient M., 13 years of age. Tomographic slices (a), perfusion map (b), and volume/time
curve (c) at dilatation cardiomyopathy: (a) tomographic slices in three projections. LV cavity widen-
ing. Visualization of moderate hypoperfusion zones in basal segments of the anterior wall and mid-
basal segments of the inferior wall. (b) 1 and 2 – “bovine eye” – diastolic and systolic perfusion. Not
previously mentioned alterations: deep and small-area hypoperfusion focus with pharmaceutic accu-
mulation decrease by more than 60 % (cardiosclerosis or ischemia); 3 LV walls’ motility. Uneven left
ventricular contractile function, the most marked hypokinesis is observed in the IVS area. (c) Low
ejection fraction (41 %; according to the automatic software data processing); end-diastolic (EDV)
and end-systolic (ESV) volume curves – late diastolic stage impairments
Thus, radionuclide diagnosis provides unique possibilities for examining condi-

tion and heart blood supply in children of different age.
18.7 Radionuclide Pulmonary Pathology Diagnosis
Radionuclide pulmonary pathology diagnosis in children helps to assess such

important parameters as pulmonary ventilation, external respiration condition,
bronchial patency, and physiological lesser circulation disorders. Perfusion pul-
monary scintigraphy (pulmonary gamma-ray imaging) is performed by means
of intravenous administration of RP – 99mTc macrotech (70–200 MBq) – and
subsequent registration of a lung image by means of a gamma-ray chamber.
Images are taken in the anteroposterior and the posterior-anterior projection
(Figs. 18.15 and 18.16).
Fig. 18.15 Perfusion scintigraphy. Patient D., 14 years of age. Hypoplasia of the left lung
Fig. 18.16 Pulmonary gamma-ray imaging. Patient O., 15 years of age. Focal alterations in both
lungs
The “interest zones” selected for processing pulmonary gamma-ray images are
upper, middle, and lower segments of each kidney. Normally, RP accumulation
degree increases evenly from lung apices to lung bases, as seen in gamma-ray
images, while the radionuclide accumulation difference between lung segments
Fig. 18.17 Patient G., 12

years of age. Spiral chest
CT. Congenital lung
malformation: hypoplasia
of the left lung. Frontal
MPR reconstruction,
pulmonary window. Left
lung volume reduction, left
mediastinal displacement.
Abnormal
angioarchitecture of the
left lung, thinned and
deformed pulmonary
vessels, decreased number
of bronchial branches,
thickened peribronchial
interstitium.
Compensatorily increased
airness of the contralateral
lung
Fig. 18.18 The same

patient (G., 12 years of
age). Pulmonary gamma-
ray imaging: hypoplasia of
the left lung: frontal
projection (right) and
posterior projection (left)
does not exceed 5–7 %. Hybrid gamma-ray images of a pediatric patient with right
lung hypoplasia and a healthy peer are given for comparison in Figs. 18.17, 18.18,
and 18.19.
Fig. 18.19 Generally

healthy child, 12 years of
age. Normal spiral chest
CT. Deformity in the
frontal projection,
pulmonary window
18.8 Radionuclide Skeletal System Pathology Diagnosis
Radionuclide skeletal system pathology diagnosis in children is performed at mul-

tiprofile pediatric inpatient hospitals far more rarely than other methods. The prin-
cipal instrumental methods of diagnosing bone diseases are radiography and
CT. They detect bone tissue demineralization, fractures, and pseudofractures well.
However, such pathological forms as osteopenia are visible in regular radiograms
only when 30–50 % of the bone mass has been lost. In this context, CT is more
informative. Along with that, bone scintigraphy is used at several forms of inflam-
matory (osteomyelitis) or metabolic bone tissue pathologies or at rare diseases in
children; it consists in administration of 99mTc technefor (250–550 MBq depend-
ing on the indication) to the patient and radionuclide examination several hours
after RP accumulation in the bon tissue, which helps to detect metabolically active
hyperfixation foci (Fig. 18.20). It ought to be mentioned that bone scintigraphy is
an irreplaceable primary method of detecting skeletal metastases, especially in
Fig. 18.20 Patient P., 15 years of age. Above: bone scintigraphy: RP accumulation in the inflam-
matory zone at osteomyelitis of the left femoral bone (arrow). Below: the same patient; CT, modes
“soft tissue window” (right) and “bone window” (left): damaged bone tissue of the left femoral
bone
patients with severe bone metastatic disease. Use of CT and MRI as diagnostic
methods is not cost-effective in the event of such pathological forms; scintigraphy
is significantly more sensitive and allows visualizing the whole skeleton
(Fig. 18.21).
a b c d
Fig. 18.21 Patient M., 13 years of age. Bone scintigraphy at hemoblastosis: increased RP accu-
mulation foci in the proximal diaphysis of the left humerus (arrow-d), the breastbone (arrows-b,c),
and the right ischium (arrow). (a, c) Frontal projection; (b, d) posterior projection
Conclusion
Nowadays, there exists an algorithm of prescribing imaging methods in pediat-
rics. Without any doubt, ultrasonography is a sort of basis of screening radiodi-
agnosis. In most cases, USD helps to reveal pathological alterations of organs
and establish correct diagnosis. Along with that, USD helps to detect patients
requiring auxiliary examination with high-technology equipment. The main
advantages of USD are high availability, low cost, and absence of radiation expo-
sure. Another valuable property is the ability to immediately determine the blood
supply mode of the area under analysis. USD helps to significantly visualize
almost all groups of lymph nodes (except for mediastinal lymph nodes). However,
one of the method’s main disadvantages is that bone tissue and air impede ultra-
sonic transmission. Along with that, it is widely acknowledged that USD is an
operator-dependent method, i.e., diagnostic information directly depends on the
physician’s qualification and experience.
Routine X-ray diagnosis, which, along with other aspects, is a peculiar type of
screening intended to detect various forms of pathologies, especially of the bone
tissue and lungs, remains common. Modern X-ray diagnostic systems have com-
pletely digitalized; this helped to significantly reduce radiation exposure and
increase diagnostic informative value.
Computed tomography represents a new cycle of development, a new genera-

tion of radiodiagnosis. In routine radiography images are two-dimensional and
linear; they represent summation of all the X-rays that have crossed through the
body. In computed tomography, we may see and point within the body. We may
obtain not only 3D, but also 4D (animated) images. Modern multislice (multispi-
ral) computed tomographs are super quick and accumulate data in 10 s or faster.
Depending on the aims and objectives of the examination, 20–40 % of children
require using intravenous contrast enhancement for computed tomography.
Contrast enhancement shows dynamic distribution of the contrast medium within
the body at different stages: arterial, venous, parenchymatous, and delayed; this
helps to differentiate between the pathological processes occurring in the body.
CT angiography (from coronary arteries and pulmonary veins to various vascular
malformations) has been becoming the gold standard. The principal disadvan-
tage of computed tomography is a rather significant radiation exposure, which
usually varies from 1.5 to 10 mSv. This is crucial for a child’s body and makes
physicians search for alternative examination methods.
Magnetic resonance imaging is a safe and highly effective non-ionizing
examination method. It is based on nuclear magnetic resonance in the presence
of static magnetic field. Radiofrequency sequences are used to obtain images.
The method features high natural tissue contrast. An extremely high space reso-
lution allows detailing the image with anatomic precision. A possibility to selec-
tively suppress water and fat in the images is successfully employed to detect
various tissue edemata. Functional MRI methods help to indirectly assess con-
tent of specific metabolites (MR spectroscopy), tissue diffusion (DWI and DTI),
and metabolic activity of brain segments (f-MRI). However, the method also
features restrictions. MRI is banned in certain groups of patients – persons with
cardio- or neurostimulators – due to the static magnetic field. Along with that,
the examination lasts for a rather long time (usually, 15–40 min) and is associ-
ated with loud noise. This makes it hardly possible in the children aged from 2
months to 5 years without anesthesia.
Scintigraphy also holds a place in this algorithm. Possibilities of this method
of lifetime imaging of a growing person’s pathophysiological and metabolic pro-
cesses are determined by development of molecular markers (tracers), which
would allow assessing distribution of individual molecular targets in tissues of
various organs, and new SPECT- and PET-based technologies of functional met-
abolic mapping at pathologies.
Our experience of such examinations indicates that in order to increase cost-
effectiveness of radionuclide diagnosis, a diagnostic imaging algorithm ought to
be used at different pathological forms in children of different age; it is also
necessary to correctly determine indications to a radionuclide examination and
adequately assess prognostic value of the information obtained by a radiologist.
A radiologist ought to have an acceptable examination strategy and objective
attitude towards the available data in order to use them for diagnostic solutions
and ensure high quality of diagnostic procedures.
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Index
A SPET/TC, 141–142
Acute tubular necrosis (ATN), 95–96 technique, 140, 141
Adenosine, 117 Biliary atresia, 76
Adrenocortical carcinoma (ACC), 343–344 Biliary cirrhosis, 160
Adult DTC. See Differentiated thyroid Biliary leak, 76, 77, 159, 160
cancer (DTC) Biologically targeted radiotherapy. See
Alanine aminotransferase (ALT), 75 Molecular radiotherapy
ALCAPA. See Anomalous origin of the left Bone marrow biopsy (BMB), 241
coronary artery from the pulmonary Bone sarcomas
artery (ALCAPA) Ewing sarcoma (ES)
ALCL. See Anaplastic large-cell lymphoma clinical presentation, 211–212
(ALCL) diagnostic workup and staging, 212
Alkaline phosphatase, 75 epidemiology, 211
Allergic enterocolitis, 163 etiology, 211
Alpha-fetoprotein (AFP), 164, 338 pathology, 212
Alveolar tumors, 280 treatment, 212–213
American Cancer Society, 24 nuclear medicine techniques vs. imaging
Anaplastic astrocytoma, 192 modalities, 296–297
Anaplastic large-cell lymphoma osteosarcoma (OS)
(ALCL), 203, 245–247 clinical presentation, 209
Ann Arbor staging system, 23, 240 diagnostic workup and staging,
Anomalous origin of the left coronary 209–210
artery from the pulmonary artery epidemiology, 209
(ALCAPA), 118 etiology, 209
Appendicitis, 153–156 pathology, 210
Aspartate aminotransferase (AST), 75 treatment and follow-up, 210–211
Athyrosis, 130 Bone scan, acute care settings
ATN. See Acute tubular necrosis (ATN) imaging technique, 97–98
Atypical teratoid/rhabdoid tumor (AT/RT), interpretation, 98–104
199–200 radiopharmaceuticals, 97–98
Bone scintigraphy (BS), 139, 145. See also
Benign bone diseases
B DSRCT, 342
B-cell NHL, 203 hepatoblastoma, 338
BEIR VII, 52, 53, 57 skeletal trauma, 100
Benign bone diseases Brain death scintigraphy
caveat and pitfalls, 142 image acquisition, 64
clinical indications, 142–146 interpretation, 64–67
sedation, 140–141 radiopharmaceutical, 64

DOI 10.1007/978-3-319-21371-2
372 Index
Brainstem tumors, 199 with genetic syndromes, 189

Brian tumors germ cell tumors (GCT), 198–199
classification, 301–302 gliomas
conventional imaging techniques, 303 high-grade histotypes, 197
diffusion tensor imaging, 303 low-grade histotypes, 197
DW-MRI, 303 lumbar puncture, 191
18
F-FDG PET, 305 medulloblastoma, 198
18
F-FDG PET-CT, 306, 307 nuclear magnetic resonance imaging
hybrid PET/MRI, 311–312 (NMRI), 191
neuroimaging, 302–303 pathology
non-FDG PET-CT embryonal neoplasms, 193
biosynthesis, 310–311 germ cell tumors, 193
cell proliferation rate, 309 gliomas, 191–192
oxygen metabolism, 311 meningiomas, 193–194
protein synthesis, 308–309 neural and mixed glioneuronal
radiolabeled amino acids, 308–309 neoplasms, 193
radiotracers, 307 pineoblastoma, 198
somatostatin receptor, 310 PNETs, 198
nuclear medicine imaging, 304–305 positron emission tomography (PET), 191
perfusion MR imaging, 303–304 treatment and follow-up
PET/CT techniques, 312–313 biological treatment, 195
Budd-Chiari syndrome, 360, 361 chemotherapy, 195
Burkitt lymphoma, 245 hydrocephalus, 194
indications, 194
radiotherapy, 194
C salvage therapy, 195–197
Cancer. See also specific types surgery, 194
environmental factors, 187 uncal (tentorial) herniation, 190
etiopathogenesis, 187 Cerebellar PNET, 198
genetic factors, 187 Cerebral tumors. See Brian tumors
incidence, 187 CH. See Congenital hypothyroidism (CH)
neoplasms, treatment for, 188 Chest X-ray, 319, 320
treatment, principles of CHI. See Congenital hyperinsulinism (CHI)
chemotherapy, 188 Cholecystitis, 74–76
radiotherapy, 188 Choledochal cyst, 159
surgery, 187–188 Choline, 310
Catechol-o-methyl transferase (COMT), 137 CNS tumors. See Central nervous system
Central nervous system (CNS) tumors (CNS) tumors
atypical teratoid/rhabdoid tumor (AT/RT), Colonic transit scintigraphy, 162–163
199–200 COMT. See Catechol-o-methyl transferase
brainstem tumors, 199 (COMT)
cerebellar (subtentorial) herniation, 190 Congenital heart disease
cerebellar PNET, 198 ALCAPA, 118
clinical presentation image acquisition, 117
brain herniation, signs of, 190 imaging algorithms, 115
endocranial hypertension, signs of, 190 Kawasaki disease, 117–118
focal signs, 190 metabolic syndromes, 119
initial signs and symptoms, 190 pulmonary blood flow, 119
ocular fundus anomalies, 190 Blalock–Taussig shunt, 121
computerized axial tomography (CT), 191 clinical indications, 122–124
diagnostic workup, 191 focal hypoperfusion, 121
ependymoma, 198 image acquisition, 121
epidemiology, 189 low-grade bronchoconstriction, 120
etiology, 189 noninvasive evaluation, 122
fluid attenuation inversion recovery patient preparation, 120
(FLAIR), 191 radiopharmaceuticals, 120
Index 373
radiopharmaceuticals, 116 Diffuse astrocytoma, 192

scintigraphy, 116 Diffuse large B cell lymphoma, 245
stress testing, 116–117 Diffusion tensor imaging (DTI), 303
TGA, 119 Diffusion-weighted magnetic resonance
Congenital hyperinsulinism imaging (DW-MRI), 298, 303
(CHI), 135–136, 161 Direct radionuclide cystography
Congenital hypothyroidism (CH), 127–131 (DRC), 178
perchlorate test, 130 Diuretic renography, 179
scintigraphy, 131 DNET. See Dysembryoplastic neuroepithelial
thyroid agenesis, 129 tumor (DNET)
thyroid ectopy, 128 Dose-rate effectiveness factor (DDREF), 53
Crohn’s disease, 151, 154 DRC. See Direct radionuclide cystography
Curie scoring system, 266 (DRC)
Cystoscintigraphy DSRCT. See Desmoplastic small-round-cell
acquisition, 178–179 tumor (DSRCT)
clinical information, 181–182 DTC. See Differentiated thyroid
processing, 179 cancer (DTC)
Duchenne muscular dystrophy (DMD), 119
Duodenitis, 163
D Dynamic renal scintigraphy
Defective thyrotropin hormone receptor acquisition, 177
(RTSH), 130 clinical information, 179
Desmoplastic infantile patient preparation, 175
astrocytoma/ganglioglioma, 193 processing, 175, 176
Desmoplastic small-round-cell tumor radiopharmaceuticals, 174–175
(DSRCT), 340–341 Dysembryoplastic neuroepithelial tumor
Differentiated thyroid cancer (DTC) (DNET), 193
clinical presentation and diagnosis, 217
dose of RAI, 328
epidemiology and etiology, 217 E
follow-up EANM. See European Association of Nuclear
advanced DTC, 333 Medicine (EANM)
elevated Tg but no evidence of Effective renal plasma flow (ERPF), 174
disease, 333 Embryonal tumors, 280
elevated Tg/recurrence on Endocrinology
RAI WBS, 332 congenital hyperinsulinism (CHI),
refractory disease, 333 135–136
serum Tg, 332 congenital hypothyroidism
genetic profiles, 318–319 (CH), 127–131
hormone manipulation, 218 hyperthyroidism, 131–132
imaging, 319–323 McCune-Albright syndrome (MAS), 135
incidence, 318 pheochromocytomas, 136–137
management, 319, 330–331 primary hyperparathyroidism, 134
pre-RIT diagnostic WBS, 325–327 toxic adenoma, 132–133
radioiodine therapy, 218 Enteric duplication cysts, 163
rhTSH, 327–328 Ependymomas, 192, 198
risk-adapted approach, 327 Epidemiology, effective dose in, 53–54
risk stratification, 327 ERPF. See Effective renal plasma
RIT. (see Radioiodine-131 ablation and flow (ERPF)
therapy (RIT)) ES. See Ewing sarcoma (ES)
special considerations, 217 ESFT. See Ewing sarcoma family tumors
staging methods, 319 (ESFT)
surgery, 218 Esophageal transit, 156–157
surgical management, 323 EuroNet-PHL-C1 trial, 242
therapy, 217–218 European Association of Nuclear Medicine
thyroid hormone suppression, 331 (EANM), 87
374 Index
Ewing sarcoma (ES) Meckel’s diverticulum (MD), 150–151

clinical presentation, 211–212 protein-losing enteropathy, 161–162
diagnostic workup and staging, 212 Germ cell tumor (GCT), 193, 198–199
epidemiology, 211 clinical presentation, 223
etiology, 211 diagnostic workup and staging, 223–224
pathology, 212 epidemiology, 222–223
pediatric sarcomas, 282, 292–296 etiology, 222–223
treatment, 212–213 pathology, 224
Ewing sarcoma family tumors (ESFT), 208 treatment, 224
External radiation therapy (XRT), 55 Germinomas, 224
GFR. See Glomerular filtration rate (GFR)
GI bleeding scintigraphy, 163
F Glioblastoma multiforme, 192
Familial medullary thyroid carcinoma Gliomas
(FMTC), 219 high-grade histotypes, 197
Fever of unknown origin (FUO) low-grade histotypes, 197
18F-FDG PET, 160 pathology, 191–192
imaging technique, 104–105 Glioneuronal papillary tumor, 193
interpretation, 105 Glomerular filtration rate (GFR), 175
radiopharmaceuticals, 104–105 Graves’ disease, 133
F18-fluorodeoxyglucose (FDG), 165
6-L-(18)F-fluorodihydroxyphenylalanine ((18)
F-DOPA), 161 H
18
F-fluoromisonidazole (18F-FMISO), 311 HB. See Hepatoblastoma (HB)
18
F-fluorothymidine (18F-FLT), 309 Hemolytic anemia, 75
FMTC. See Familial medullary thyroid Hemolytic uremic syndrome, 163
carcinoma (FMTC) Henoch-Schonlein purpura, 163
Follicular thyroid carcinoma (FTC), 217 Hepatobiliary scintigraphy, 158–160
18
F-sodium fluoride (NaF), 97 abdominal pain, 75
FTC. See Follicular thyroid carcinoma (FTC) acute cholecystitis, 74–76
Functional fecal retention, 162 alanine aminotransferase (ALT), 75
Functional radionuclide kidney examination, alkaline phosphatase, 75
354–356 aspartate aminotransferase (AST), 75
FUO. See Feof unknown origin (FUO) vs. biliary atresia, 76
biliary leak, 76
bilirubin, 75
G hemolytic anemia, 75
Gangliocytoma, 193 imaging technique, 76–77
Ganglioglioma, 193 interpretation, 77–83
Gastric emptying, 157–158 radiopharmaceuticals, 76–77
Gastritis, 163 total parenteral nutrition (TPN), 75
Gastroesophageal reflux, 156 Hepatoblastoma (HB), 164–165, 338–339
Gastrointestinal (GI) bleeding, 163–164 clinical presentation, 231
Gastrointestinal diseases diagnostic workup and staging, 231
appendicitis, 153–156 epidemiology, 230–231
colonic transit, 162–163 etiology, 230–231
esophageal transit, 156–157 pathology, 232
gastric emptying, 157–158 treatment, 232
gastroesophageal reflux, 156 Hepatoscintigraphy, 357–359, 361
gastrointestinal (GI) bleeding, 163–164 HN. See Hydronephrosis (HN)
hepatobiliary scintigraphy, 158–160 Hodgkin lymphoma (HL)
hepatoblastoma (HB), 164–165 advanced-stage, 242
hyperinsulinism, 161 Ann Arbor classification, 240
inflammatory bowel diseases (IBD), B symptoms, 239
151–155 chemotherapy, 242–244
Index 375
classical, 240 L
epidemiology, 201 Langerhans cell histiocytosis (LCH), 342–343
incidence, 239 clinical presentation, 228–229
limited-stage, 242 diagnosis and staging, 229–230
pathology, 203 epidemiology, 228
posttreatment evaluation, 242 etiology, 228
prognosis, 240 pathology, 230
Reed-Sternberg cells, 239 therapy, 230
response criteria, 242 LBL. See Lymphoblastic lymphoma (LBL)
risk factors, 240 LCH. See Langerhans cell histiocytosis (LCH)
staging, 240–242 L-dihydroxyphenylalanine (L-DOPA), 161
treatment, 204 L-DOPA. See L-dihydroxyphenylalanine
WHO classification, 240 (L-DOPA)
Homovanillic acid (HVA), 256 Legg-Calvé-Perthes (LCP) disease, 99
Hybrid gamma-ray images, 365 Linear no-threshold (LNT) model, 52–53
Hydronephrosis (HN), 173 Lower gastrointestinal (GI) bleeding, 80–81
Hyperinsulinism, 161 Lugano classification, 242, 243
Hyperthyroidism, 131–133 Lung, 119
Hypoplasia, 130 Blalock–Taussig shunt, 121
clinical indications, 122–124
focal hypoperfusion, 121
I image acquisition, 121
IBD. See Inflammatory bowel low-grade bronchoconstriction, 120
diseases (IBD) noninvasive evaluation, 122
ICRP, 52, 53 patient preparation, 120
131
I diagnostic WBS, 325, 326 radiopharmaceuticals, 120
123
I-labelled MIBG, 258, 260, 264, 265 Lymphoblastic lymphoma
123
I-metaiodobenzylguanidine (MIBG) (LBL), 203, 245, 247
imaging, 24 Lymphoepithelioma. See Undifferentiated
131
I-MIBG therapy carcinoma
combination methods, 271–272 Lymphomas. See also Hodgkin lymphoma
front-line therapy, 271 (HL); Non-Hodgkin lymphoma
monotherapy, 271 (NHL)
procedure, 270 clinical presentation, 201
radiopharmaceutical, 270 diagnosis, 201–202
side effects, 272–273 epidemiology
111
In-DTPA-octreotide, 310 Hodgkin lymphoma (HL), 201
Infectious enterocolitis, 163 non-Hodgkin lymphoma (NHL),
Inflammatory bowel diseases 200–201
(IBD), 151–155, 163 pathology
International Neuroblastoma Risk Group Hodgkin lymphoma (HL), 203
(INRG), 214 non-Hodgkin lymphoma (NHL),
International Neuroblastoma 202–203
Risk Group Staging System PET, 201–202
(INRGSS), 215, 256, 257 staging, 201
International Neuroblastoma Staging System technical aspects
(INSS) tumour stages, 256, 257 18F-FDG PET/CT imaging, 248–250
Ionizing radiation, 52 PET/CT acquisition, 250
123
I-ortho-iodo-hippurate (123I-hippuran), 174 scan acquisition, 250
123
I whole-body scintigraphy sedation/anesthesia, 249
(WBS), 325, 326 tracer injection, 249
treatment
Hodgkin lymphoma (HL), 204
K non-Hodgkin lymphoma (NHL),
Kawasaki disease, 117–118 203–204
376 Index
M iodine-131 meta-iodobenzylguanidine
Malignant germinomatous germ cell tumors (mIBG), 39–40
177
(MNGGCT), 224 Lu-DOTATATE, 41–42
Mallory-Weiss tear, 163 refractory and relapsed high-risk, 39
MAO. See Monoamine oxidase (MAO) neuroendocrine cancers, 43–46
MAS. See McCune-Albright syndrome (MAS) radiation protection, 34–35
McCune-Albright syndrome (MAS), 135 staffing and facilities, 32–34
MD. See Meckel’s diticulum (MD) thyroid cancer, 35–38
Meckel scan Monoamine oxidase (MAO), 137
imaging technique, 82–84 Monostotic LCH, 230
interpretation, 84–86 MTC. See Medullary thyroid carcinoma
radiopharmaceuticals, 82–84 (MTC)
Meckel’s diverticulum (MD), 81, 84 Multiple endocrine neoplasia (MEN), 136, 219
ectopic gastric mucosa in, 150–151 Multisystem LCH, 230
Medical exposure MYCN. amplification, 214
radiation risk Myeloablative chemotherapy, 38
Chernobyl accident, 56–57 Myocardial perfusion scintigraphy, 359
in children, 57
I-131, diagnostic exposure of, 54–56
Japanese atomic bomb, 56–57 N
risk definitions N-acetyl aspartate (NAA), 304
effective dose, 53–54 Nasopharyngeal carcinoma (NPC)
linear no-threshold (LNT) clinical presentation, 225
model, 52–53 diagnosis
Medullary thyroid carcinoma (MTC), 219 pathology, 225
Medulloblastomas, 193, 198 staging, 225
Melanoma epidemiology, 224
clinical presentation, 220 treatment and prognosis, 226
diagnosis, 220 Negative predictive value (NPV), 248
epidemiology and etiology, 219–220 Neoplasms
therapy, 220 adrenocortical carcinoma, 343–344
MEN. See Multiple endocrine neoplasia (MEN) desmoplastic small-round-cell
Meningiomas, 193–194 tumor, 340–341
Metaiodobenzylguanidine (MIBG) hepatoblastoma, 338–339
scintigraphy, 256–258 Langerhans cell histiocytosis, 342–343
administered activity, 260 Nephroblastoma. See Wilms’ tumor
bilateral symmetrical activity, 261, 262 Nephroscintigraphy, 354–356
clinical indications, 266 Nephro-urology
diagnostic management, 263–264 clinical context, 173
false-negative finding, 261–262 nuclear medicine procedures
false-positive results, 261–262 clinical informations, 179–182
instrument specifications, 260 cystoscintigraphy, 178–179
preparation and interference, 259 dynamic renal scintigraphy, 174–176
prognostic significance, 266 static renal scintigraphy, 176–178
radiopharmaceutical, 258 techniques, 174
SPECT, 260–261 Neuroblastoma (NB)
Midgut volvulus, 163 biological-molecular characterization, 214
MNGGCT. See Malignant germinomatous chemotherapy, 216
germ cell tumors (MNGGCT) diagnostic procedures, 215
Molecular radiotherapy diagnostic tools, 258
challenges of, 46 diagnostic workup and staging, 214–216
children with cancer, care of, 31–32 epidemiology, 213
neuroblastoma etiology, 213
dose-dense platinum-based induction evaluation, 256
131
chemotherapy, 38 I-MIBG therapy
Index 377
combination methods, 271–272 etiology, 209

front-line therapy, 271 pathology, 210
monotherapy, 271 pediatric sarcomas, 281, 289–291
procedure, 270 treatment and follow-up, 210–211
radiopharmaceutical, 270
side effects, 272–273
INRGSS, 256, 257 P
INSS tumour stages, 256 Papillary thyroid carcinoma (PTC), 217
MIBG scintigraphy, 256–258 (see also 1p deletion, 214
Metaiodobenzylguanidine (MIBG) PE. See Pulmonary emboli (PE)
scintigraphy) Pediatric diseases, available diagnostic tools
primordial neural crest cells, 256 in, 20
prognostic factors, 215 Pediatric sarcomas
radiation treatment, 216 combined PET/MRI, 298
radiopharmaceuticals for PET, 266 definition, 280
18
F-DOPA PET/CT, 268 Ewing sarcoma, 282, 292–296
18
F-FDG PET/CT, 267 FDG PET/CT, 296, 298
risk stratification, 269–270 imaging test, 282–288, 296
surgery, 216 osteosarcoma, 281, 289–291
sympathetic nervous system, 256 rhabdomyosarcoma, 280–281
treatment, 216 Pheochromocytomas, 136–137
Neurocytoma, 193 Pilocytic astrocytoma, 192
NHL. See Non-Hodgkin lymphoma (NHL) Pineoblastoma, 198
Nodular lymphoid hyperplasia, 163 PIOPED. See Prospective Investigation of
Non-cerebellar PNETs, 193 Pulmonary Embolism Diagnosis
Non-Hodgkin lymphoma (NHL) (PIOPED)
B cell immunophenotype, 245 Plummer disease, 133
categories, 245 Polyostotic LCH, 230
epidemiology, 200–201 Polyps, 163
pathology, 202–203 Positive predictive value (PPV), 247
prospective trials, 248 Positron emission tomography (PET), 161
staging, 245–247 radiopharmaceuticals for NB, 266
18
treatment, 203–204, 247 F-DOPA PET/CT, 268
18
Non-rhabdomyosarcoma sarcomas F-FDG PET/CT, 267
(non-rhabdo) Positron emission tomography/magnetic
chemotherapy, 208 resonance (PET/MR)
diagnostic workup and staging, 207 cardiac disorders, 24
epidemiology, 206–207 fever, 24–25
etiology, 206–207 inflammation of unknown origin, 24–25
pathology, 207–208 neurological disorders
radiotherapy, 208 brain tumors, 22–23
surgery, 208 epilepsy, 21
treatment and follow-up, 208 tuberous sclerosis complex, 22
NPC. See Nasopharyngeal carcinoma (NPC) oncological and hematological disorders
Nuclear medicine (NM) histiocytosis, 23–24
description, 350–352 lymphoma, 23
Scientific Center of Children’s Health neuroblastoma, 24–25
(SCCH), 352–353 pediatric sarcomas, 298
Pre-radioiodine diagnostic whole-body
scintigraphy (WBS), 325–327
O Primary hyperparathyroidism, 134
Osteosarcoma (OS) Prospective Investigation of Pulmonary
clinical presentation, 209 Embolism Diagnosis
diagnostic workup and staging, 209–210 (PIOPED), 73–74
epidemiology, 209 Protein-losing enteropathy, 161–162
378 Index
PTC. See Papillary thyroid carcinoma (PTC) RB. See Retinoblastoma (RB)
Pulmonary emboli (PE), 67–68 Recombinant thyrotropin (rhTSH), 327–328
Pulmonary fibrosis, 330 Reed-Sternberg (RS) cells, 201, 203, 239
Pulmonary gamma-ray images, 363–365 Regions of interest (ROI), 175
Renal cortical imaging, pyelonephritis
imaging technique, 89–90
Q interpretation, 90–93
99m
11q deletion, 214 Tc-dimercaptosuccinic acid (99mTc-DMSA), 89
17q, trisomy or polysomy of portions of, 214 radiopharmaceuticals, 89–90
urinary tract infection (UTI), 88–89
Renal scan, 88
R Renal transplant, 91, 94
Radiation Effects Research Foundation, 51 imaging technique, 94–95
Radiation exposure, 56–57 interpretation, 95–97
Radiation risk, 57. See also Medical exposure radiopharmaceuticals, 94–95
Radioactive iodine (RAI) Retinoblastoma (RB)
paediatric dose, 328 clinical presentation, 226–227
therapy, 131–132 diagnostic workup and staging, 227
Radiodiagnosis, 349–350 epidemiology, 226
Radioiodine-131 ablation and therapy (RIT) etiology, 226
destroying microscopic disease, 323 pathology, 227
direct adverse effects, 330 treatment, 228
nodal metastases, 324 Rhabdomyosarcoma (RMS)
pulmonary fibrosis, 330 chemotherapy, 206
pulmonary metastases, 324 clinical presentation, 204
reproductive issues, 329–330 diagnostic workup and staging, 205
residual disease, 323 epidemiology, 204
role of, 324 etiology, 204
second primary malignancy, 329 pediatric sarcomas, 283–287
Radionuclide diagnosis alveolar tumors, 280
cardiac pathology, 358–363 embryonal tumors, 280
hepatography, 357–358 regional lymph node, 280
kidney examination, 354–356 risk classification, 280–281
pulmonary pathology, 363–366 radiotherapy, 206
skeletal system pathology, 366–368 soft tissue sarcomas, 297–298
Radionuclide therapy. See Molecular surgery, 206
radiotherapy treatment and follow-up, 206
Radiopharmaceuticals. See also Benign bone rhTSH. See Recombinant thyrotropin (rhTSH)
diseases RMS. See Rhabdomyosarcoma (RMS)
congenital heart disease, 116
dynamic renal scintigraphy, 174–175
131
I-MIBG therapy, 270 S
interpretation, 72–74 Scientific Center of Children’s Health
MIBG scintigraphy, 258 (SCCH), 352–353
perfusion agent, 69–70 Second primary malignancy (SPM), 329
for PET, 266 Single-photon emission tomography (SPECT),
18
F-DOPA PET/CT, 268 20, 65
18
F-FDG PET/CT, 267 MIBG scintigraphy, 260–261
pulmonary blood flow, 120 SIOPEN score, 266
static renal scintigraphy, 177 Skeletal trauma, 100
ventilation agents Sodium iodide symporter (NIS), 130, 318
81m
krypton, 71 Soft tissue sarcomas, 297–298. See also
99m
Tc-DTPA aerosol, 70 Rhabdomyosarcoma (RMS)
99m
Tc-technegas, 71 Somatostatin, 310
133
xenon, 70–71 SPECT. See Single-photon emission
RAI. See Radioactive iodine (RAI) tomography (SPECT)
Index 379
Static renal scintigraphy clinical presentation and diagnosis, 217

acquisition, 177 epidemiology and etiology, 217
clinical informations, 179–181 hormone manipulation, 218
patient preparation, 177 radioiodine therapy, 218
processing, 177–178 special considerations, 217
radiopharmaceuticals, 177 surgery, 218
therapy, 217–218
medullary thyroid carcinoma (MTC), 219
T molecular radiotherapy, 35–38
Taurine, 304 Thyroid dysgenesis (TD), 127
99m
Tc-diethylene triamine pentaacetic acid Thyroidectomy, 36, 132
(99mTC-DTPA), 88 Thyroid ectopy, 128
99m
Tc-diethylene-triaminepentaacetic acid Thyroid hormone suppression, 331
(DTPA), 174 Thyroid scintigraphy (TS), 128
99m
Tc-dimercaptosuccinic acid Tibial diaphysis, 100, 101
(99mTc-DMSA), 88 Total parenteral nutrition (TPN), 75
99m
Tc-diphosphonates, 258 Total thyroidectomy, 323
99m
Tc-disofenin (DISIDA), 76 Toxic adenoma, 132–133
99m
Tc-ethylcysteinate dimer TPN. See Total parenteral nutrition (TPN)
(99mTc-ECD), 64 Transposition of the great arteries (TGA), 119
99m
Tc-etylen-cistein (EC), 174 TS. See Thyroid scintigraphy (TS)
99m
Tc-glucoheptonate (99mTc-GH), 90 Tumor hypoxia, 311
99m
Tc-hexamethylpropyleneamine oxime
(99mTc-HMPAO), 64
99m
Tc-hexamethylpropyleneamine oxime U
(HMPAO), 151 Ulcerative colitis, 151
99m
Tc-labeled radiopharmaceuticals, 20 Undifferentiated carcinoma, 225
99m
Tc-macroaggregated albumin Unifocal eosinophilic granuloma, 229
(99mTc-MAA), 69 United Nations Scientific Committee on the
99m
Tc-mebrofenin (BrIDA), 76 Effects of Atomic Radiation
99m
Tc-mercaptoacetyltriglycine (99mTC-MAG3), (UNSCEAR), 52, 53, 57
88, 174 Upper urinary tract infections (UTI), 173
99m
Tc-methylene diphosphonate Ursodeoxycholic acid, 77
(99mTc-MDP), 97 UTI. See Upper urinary tract
99m
Tc-red blood cell (RBC) scintigraphy, 163 infections (UTI)
imaging technique, 87
interpretation, 88
radiopharmaceuticals, 87 V
99m
Tc-sestamibi, 305 Vanillylmandelic acid (VMA), 256
99m
Tc technefor, 366 Vascular malformations, 163
99m
Tc technephyte, 357, 361 Ventilation/perfusion scan (V/Q scan), 68
TD. See Thyroid dysgenesis (TD) Vesicoureteral reflux (VUR), 173, 354–355
99m
Technetium-dimercaptosuccinic acid
(DMSA), 177
TGA. See Transposition of the great arteries W
(TGA) White blood cell (WBC), 104.105
Thrombocytopenia, 272 Wilms’ tumor
Thyroid agenesis, 129 chemotherapy, 222
Thyroidal ontogeny, 127 clinical presentation, 221
Thyroid cancer. See also Differentiated thyroid diagnostic workup and staging, 221
cancer (DTC) epidemiology, 220–221
caused by etiology, 220–221
Chernobyl accident, 56–57 pathology, 221–222
I-131, diagnostic exposure of, 54–56 radiotherapy, 222
Japanese atomic bomb, 56–57 surgery, 222
differentiated thyroid carcinoma (DTC) treatment, 222
380 Index
World Health Organization (WHO) desmoplastic infantile astrocytoma/

classification ganglioglioma, 193
CNS tumors, histological classification, diffuse astrocytoma, 192
192 high-grade astrocytomas, 189
Hodgkin lymphoma, 240 pilocytic astrocytoma, 192
lymphoproliferative diseases, 202
epilepsy, report of, 21
grade X
anaplastic astrocytoma, 192 XRT. See External radiation therapy (XRT)

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Clinical Nuclear

Egesta Lopci Arturo Chiti

ISBN 978-3-319-21370-5 ISBN 978-3-319-21371-2 (eBook)

Library of Congress Control Number: 2015953158

Springer Cham Heidelberg New York Dordrecht London

Printed on acid-free paper

Springer International Publishing AG Switzerland is part of Springer Science+Business Media

Life-threatening disease is rare in pediatric patients. When it occurs it is complex

1 Peculiar Aspects and Problems of Diagnostic

Luigi Mansi, Vincenzo Cuccurullo, and Maria Rosaria Prisco

© Springer International Publishing Switzerland 2016 1

1.1 Nuclear Medicine as Molecular Imaging

term is actually more frequently referred to advanced procedures, mainly preclinical

1.2 Cost/Effectiveness in Diagnostic Imaging

A cost-effectiveness analysis (CEA) evaluates relative costs and outcomes in the

1.3 Cost/Effectiveness of Nuclear Medicine in Paediatrics

Table 1.1 Conditions determining Its own capabilities and limitations

1.3.1 General Capabilities of NM

In the paragraphs above, we described how effective nuclear medicine can be

1.3.2 General Limitations of Nuclear Medicine

Being based on difference of concentration and not of density, NM cannot give an

1.4 Technical Problems of NM in Paediatrics

1.4.1 How to Approach the Paediatric Patient in Nuclear

In paediatric imaging, a successful diagnostic examination is obtained when the

1.4.2 The Paediatric Environment in Nuclear Medicine

1.4.3 Patient Preparation

1.4.4 Patient Positioning

This is a major technical issue in paediatric imaging, because a correct position is

1.4.5 Patient Restraining

1.4.6 Sedation (and Narcosis)

Being radionuclide procedures based on pathophysiological premises, sedation may

1.4.7 Radioactive Dose

This book is presenting a specific chapter on dosimetry. Here we want only to

1.4.8 Image Acquisition and Other Technical Points

1.5 Nuclear Medicine in Paediatrics as Compared

As it can be derived from Table 1.1, the role of NM in paediatrics is dependent on

1.5.1 Risks and Prejudices

In the definition of a cost/effective balance in paediatrics, remembering the funda-

1.5.2 Peculiarities of Alternative Diagnostic Procedures

As noted many times above, in the definition of a cost/effective balance nuclear

further procedures to complete the diagnostic course. A major problem is dependent

1.6 Nuclear Medicine in the Diagnostic Scenario

As described above, the diagnostic scenario in paediatrics is occupied by very effec-

7. Furlow B (2011) Radiation protection in pediatric imaging. Radiol Technol 82(5):421–439

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overcome some of the limitations of current PET/computed tomography (CT) scan,

2.2 Available Diagnostic Tools in Pediatric Diseases

Nuclear medicine procedures are able to address several childhood diseases in

2.3 PET/MR in Pediatric Patients

2.3.1 Neurological Disorders

2.3.1.2 Tuberous Sclerosis Complex

2.3.1.3 Brain Tumors

2.3.2 Oncological and Hematological Disorders

the study of morphological findings with functional and metabolic information in

2.3.3 Cardiac Disorders

A hybrid PET/MR approach is also promising in pediatric population for early

2.3.4 Fever and Inflammation of Unknown Origin

The approach of combined PET/MR with various MR techniques may be beneficial

29. Montravers F, McNamara D, Landman-Parker J et al (2002) [18F]FDG in childhood lym-

3.1 Molecular Radiotherapy

Molecular radiotherapy, sometimes also called radionuclide therapy or biologically

M.N. Gaze (*) • J.E. Gains

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